Dimethyl Fumarate and Vaccination Regimens

ABSTRACT

Provided herein is a method of treating or preventing a disease or disorder (e.g., MS) in a subject in need thereof, comprising (a) administering to the subject a first dose of a pharmaceutical composition comprising a fumarate agent (e.g., DMF) for a first dosing period; (b) administering a vaccine; and (c) administering to the subject a second dose of the pharmaceutical composition for a second dosing period.

This application claims the benefit of U.S. provisional application No.61/953,259 filed Mar. 14, 2014, which is incorporated by referenceherein in its entirety.

1. FIELD OF INVENTION

The present invention generally relates to methods of treating orpreventing a neurological disease or disorder (e.g., multiple sclerosis)in a subject who receives a vaccine.

2. BACKGROUND OF THE INVENTION

TECFIDERA™ has been approved by the U.S. Food and Drug Administrationfor the treatment of patients with relapsing forms of multiple sclerosis(MS). TECFIDERA™ contains dimethyl fumarate (DMF), which has thefollowing structure:

The starting dose for TECFIDERA™ is 120 mg twice a day orally. After 7days, the dose is to be increased to the maintenance dose of 240 mgtwice a day orally. TECFIDERA™ can be taken with or without food.

Vaccines are an important class of medications that are frequently usedfor treating or preventing various diseases, such as infectiousdiseases. Patients having MS can receive one or more vaccines prior toor during treatments with DMF. One objective of the present invention isto provide a method of treating or preventing multiple sclerosis inpatients who receive a vaccine.

3. BRIEF SUMMARY OF THE INVENTION

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate        (“MMF”), a compound that metabolizes into monomethyl fumarate in        vivo, a deuterated analog thereof, a pharmaceutically acceptable        salt thereof, and a combination thereof;    -   (b) administering a vaccine to the subject; and    -   (c) administering to the subject a second dose of the        pharmaceutical composition for a second dosing period, wherein        the second dosing period is after the first dosing period,        stopping administration of the pharmaceutical composition (i.e.,        the second dose can be null). In some embodiments, the subject        is administered the same amount of fumarate agent as in the        first dosing period after the second dosing period.

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof, and wherein the subject        receives a vaccine;    -   (b) determining an immune response of the subject to the vaccine        before the end of the first dosing period; and    -   (c) adjusting the first dose to a second dose of the        pharmaceutical composition, which includes stopping        administration of the pharmaceutical composition (i.e., the        second dose can be null), based on the immune response        determined in step (b).

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof, and wherein the subject        receives a vaccine;    -   (b) determining an immune response of the subject to the vaccine        before the end of the first dosing period; and    -   (c) administering to the subject a second dose of the        pharmaceutical composition for a second dosing period. In some        embodiments, the second dose is equal to or less than the first        dose. In some embodiments, the subject is administered the same        amount of fumarate agent as in the first dosing period after the        second dosing period.

In some embodiments, the first or second dose of the pharmaceuticalcomposition contains a therapeutically effective amount of the fumarateagent. In some embodiments, the fumarate agent comprises MMF, DMF, or acombination thereof. In some embodiments, the fumarate agent comprisesDMF. In some embodiments, the only active ingredient in thepharmaceutical composition is DMF. In some embodiments, the first doseis a daily amount of about 480 mg dimethyl fumarate administered twiceper day (BID). In some embodiments, the second dose is about 0 mg toabout 480 mg fumarate agent (e.g., DMF).

In some embodiments, the step of determining the immune responsecomprises obtaining serum antibody (e.g., IgG or IgM) levels in thesubject induced by the vaccine post-immunization (e.g., 4 weeks afterimmunization), obtaining the serum antibody (e.g., IgG or IgM) levels inthe subject pre-immunization, and comparing the serum antibody levels inthe subject pre- and post-immunization. In some embodiments, the serumantibody is IgG against tetanus diphtheria toxoids, keyhole limpethemocyanin, or pneumovax-23, and the scrum IgG level in the subjectincreases less than 4-fold (e.g., less than 3-fold or less than 2-fold)from pre-vaccination to 4 weeks after vaccination. In some embodiments,the serum IgG level in the subject increases at least 2-fold (e.g., atleast 4-fold or at least 10-fold) from pre-immunization to 4 weeks afterimmunization.

The immune response following vaccination, e.g., as determined by thedetermining step, can affect the second dose. In some embodiments, theimmune response of the subject to the vaccine is characterized in thatthe serum antibody level induced by the vaccine in the subject increasesless than 4-fold (e.g., less than 3-fold or less than 2-fold) frompre-vaccination to 4 weeks after vaccination, and the second dose isabout 5% to about 95% (e.g., about 10%, about 20%, about 30%, about 40%,about 50%, about 60%, about 70%, about 80%, about 90%, or any rangesthereof) of the first dose. In some embodiments, the second dose is adaily dose of about 0 to about 480 mg. In some embodiments, the immuneresponse of the subject to the vaccine is characterized in that theserum antibody level in the subject increases at least 2-fold (e.g., atleast 4-fold or at least 10-fold) from pre-immunization to 4 weeks afterimmunization, and the second dose is the same as the first dose.

In some embodiments, the methods described herein further compriseadministering a titration dose of the pharmaceutical composition priorto the first and/or second dosing periods. In some embodiments, thetitration dose is administered to the subject for at least 7 days priorto beginning the first and/or second dosing period. In some embodiments,the fumarate agent is DMF and the titration dose is a daily dose ofabout 240 mg DMF administered BID for 7 consecutive days. In someembodiments, the fumarate agent is DMF and the titration dose is a dailydose of 360 mg DMF administered three times a day.

In some embodiments, the invention also provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject who receives avaccine, comprising screening a plurality of doses of a pharmaceuticalcomposition comprising a fumarate agent selected from the groupconsisting of monomethyl fumarate, a compound that metabolizes intomonomethyl fumarate in vivo, a deuterated analog thereof, apharmaceutically acceptable salt thereof, and a combination thereof, by

-   -   (1) identifying a first group of subjects and at least a second        group of subjects, wherein both the first and second groups of        subjects receive a vaccine, wherein the first group of subjects        is treated with a first dose of the pharmaceutical composition,        and the second group of subjects is treated with a second dose        of the pharmaceutical composition; and    -   (2) determining a lower risk dose. In some embodiments, the        method further comprises administering the lower risk dose of        the pharmaceutical composition to the subject. In some        embodiments, the lower risk dose is determined by comparing        immune responses to the vaccine between the first and second        groups of subjects.

In some embodiments, the invention provides a method of treating orpreventing multiple sclerosis in a subject in need thereof, comprising

-   -   (a) determining a subject's baseline lymphocyte count prior to        treatment;    -   (b) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof;    -   (c) determining a subject's total lymphocyte count after the        first dosing period; and    -   (d) if the lymphocyte count after the first dosing period is        about 90% of the baseline lymphocyte count or lower, do not        administer tetanus diphtheria toxoids vaccine, keyhole limpet        hemocyanin vaccine, pneumovax-23 vaccine, or any combinations        thereof.

In some embodiments, the invention provides a method of treatingmultiple sclerosis in a human subject in need thereof comprising

-   -   (a) administering a therapeutically effective amount of dimethyl        fumarate to the subject; and    -   (b) administering a vaccine to the subject.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

As used herein, “a” or “an” means one or more unless otherwisespecified.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example, within 20% of the stated value. As used herein,“about” a specific value also includes the specific value, for example,about 10% includes 10%.

As used herein, the term “DMF,” or “BG00012” refers to the compounddimethyl fumarate. The term “MMF” refers to the compound, or an ionizedform of, monomethyl fumarate.

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disease or disorder.

The term “prophylaxis”, the term “prophylactic treatment”, or“preventing” refers to precluding a patient from getting a disorder,causing a patient to remain free of a disorder for a longer period oftime, or halting the progression of a disorder, to either astatistically significant degree or to a degree detectable to oneskilled in the art.

The terms “therapeutically effective dose” and “therapeuticallyeffective amount” refer to that amount of a compound which results inprevention or delay of onset or amelioration of symptoms of aneurological disorder in a subject or an attainment of a desiredbiological outcome, such as reduced neurodegeneration (e.g.,demyelination, axonal loss, or neuronal death) or slowing in theaccumulation of physical disability (e.g., as indicated by, e.g., areduced rate of worsening of a clinical score (e.g., Enhanced DisabilityStatus Scale (“EDSS”)) or another suitable parameter indicating diseasestate. Exemplary disease state parameters include the number of clinicalrelapses, number of T1 lesions, reduced mean number of new and totalgadolinium-enhancing (Gd+) lesions on brain MRI scans, number and volumeof new or newly-enlarging T2 hyperintense lesions, number of new T1hypointense lesions, percentage of Gd+ lesions that convert to T1hypointense lesions, measures of atrophy and magnetization transferratio, and the like).

The term “microtablet” means a compact in the form of a small (micro)tablet having a mean diameter of less than 5,000 microns (e.g., about1,000 microns to about 3,000 microns), excluding any coating, thatcomprises the active ingredient(s) and one or more excipients. Theactive ingredient(s) and excipients can be homogeneously orheterogeneously mixed in the microtablet. In any of the embodimentsdescribed herein, the microtablets may be coated, for example, by a sealcoating, an enteric coating, or a combination thereof.

As used herein, when an object (e.g., a microtablet) is said to be“coated” or have a “coating,” it is to be understood that the object canbe fully or partially coated by one or more coatings. Similarly, when anobject (e.g., a microtablet) is said to be “encapsulated,” it is to beunderstood that the object can be fully or partially encapsulated.

The term “subject” as used herein generally refers to human, includinghealthy human or a patient with certain diseases or disorders (e.g.,MS).

4.2 Compounds that can be Metabolized into MMF

A compound that can be metabolized into MMF in vivo, as used herein,includes DMF. A compound that can be metabolized into MMF in vivo, asused herein, includes any such compound known in the art. For example, acompound that can be metabolized into MMF in vivo, as used hereinincludes, for example, any compound described in U.S. application Ser.No. 13/760,916, the content of which is incorporated herein by referencein its entirety.

Compounds that can be metabolized into MMF in vivo include compounds ofFormula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   R¹ and R² are independently chosen from hydrogen, C₁₋₆ alkyl,        and substituted C₁₋₆ alkyl;    -   R³ and R⁴ are independently chosen from hydrogen, C₁₋₆ alkyl,        substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆        heteroalkyl, C₄₋₁₂ cycloalkylalkyl, substituted C₄₋₁₂        cycloalkylalkyl, C₇₋₁₂ arylalkyl, and substituted C₇₋₁₂        arylalkyl; or R³ and R⁴ together with the nitrogen to which they        are bonded form a ring chosen from a C₅₋₁₀ heteroaryl,        substituted C₅₋₁₀ heteroaryl, C₅₋₁₀ heterocycloalkyl, and        substituted C₅₋₁₀ heterocycloalkyl; and    -   R⁵ is chosen from methyl, ethyl, and C₃₋₆ alkyl;    -   wherein each substituent group is independently chosen from        halogen, —OH, —CN, CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹,        —OR¹¹, —C(O)R¹¹, —COOR¹¹, and —NR¹¹ ₂ wherein each is        independently chosen from hydrogen and C₁₋₄ alkyl; with the        proviso that when R⁵ is ethyl; then R³ and R⁴ are independently        chosen from hydrogen, C₁₋₆ alkyl, and substituted C₁₋₆ alkyl.

Useful examples of a compound of Formula (I) include:(N,N-diethylcarbamoyl)methyl methyl(2E)b3ut-2-ene-1,4-dioate;methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate; methyl2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;(N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-dioate;2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino} acetic acid;4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino butanoic acid;methyl(N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl(2E)but-2ene-1,4-dioate;(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;(N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;bis-(2-methoxyethylamino)carbamoyl]methylmethyl(2E)but-2-ene-1,4-dioate; [N-(methoxycarbonyl)carbamoyl]methylmethyl(2E)but-2ene-1,4-dioate;4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic acid,sodium salt; methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate;methyl 2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl(2E)but-2ene-1,4-dioate;{N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2ene-1,4dioate; methyl2-(4-methylpiperazinyl)-2-oxoethyl(2E)but-2-ene-1,4-dioate; methyl{N-[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2ene-1,4-dioate;2-(4-acetylpiperazinyl)-2-oxoethyl methyl(2E)but-2ene-1,4-dioate;{N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl(2E)but-2-ene-1,4-dioate; methyl2-(4-benzylpiperazinyl)-2-oxoethyl(2E)but-2-ene-1,4-dioate;[N,N-bis(2-ethoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-dioate;2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethylmethyl(2E)but-2ene-1,4-dioate;1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-carboxylic acid;(N-{[tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methylmethyl(2E)but-2-ene1,4-dioate;{N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methylmethyl(2E)but-2-ene-1,4-dioate; methyl1-methyl-2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl(2E)but-2-ene-1,4-dioate;(N,N-dimethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-dioate;2-{2-[(2E)-3-(methoxy carbonyl)prop-2-enoyloxyl]-N-methylacetylamino)acetic acid; (N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methylmethyl(2E)but-2-ene-1,4-dioate;(2E)but-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl(2E)but-2-ene-1,4-dioate;{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methylmethyl(2E)but-2-ene-1,4-dioate;{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl} ethylmethyl(2E)but-2-ene-1,4-dioate;{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl} ethylmethyl(2E)but-2-ene-1,4-dioate;(1S)-1-methyl-2-morpholin-4-yl-2-oxoethylmethyl(2E)but-2-ene-1,4-dioate;(1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethylmethyl(2E)but-2-ene-1,4-dioate; (1R)-1-(N,N-diethylcarbamoyl)ethylmethyl(2E)but-2-ene-1,4-dioate; and a pharmaceutically acceptable saltof any of the foregoing.

Useful examples of a compound of Formula (I) also include:(N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate; methyl2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;(N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;[N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-dioate;2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino} acetic acid;{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic acid;methyl(N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl(2E)but-2ene-1,4-dioate;(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;(N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;bis-(2-methoxyethylamino)carbamoyl]methylmethyl(2E)but-2-ene-1,4-dioate; [N-(methoxycarbonyl)carbamoyl]methylmethyl(2E)but-2ene-1,4-dioate; methyl2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate; methyl2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl(2E)but-2ene-1,4-dioate;{N-[2-(dimethylamino)ethyl]carbamoyl]methylmethyl(2E)but-2ene-1,4-dioate;(N-[(methoxycarbonyl)ethyl]carbamoyl)methylmethyl(2E)but-2-ene-1,4-dioate;2-{2-1(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoicacid; and a pharmaceutically acceptable salt of any of the foregoing.

Compounds that can be metabolized into MMF in vivo also includecompounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R⁶ is chosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆        heteroalkyl, substituted C₁₋₆ heteroalkyl, C₃₋₈ cycloalkyl,        substituted C₃₋₈ cycloalkyl, C_(6-s) aryl, substituted C₆₋₈        aryl, and —OR¹⁰ wherein R¹⁰ is chosen from C₁₋₆ alkyl,        substituted C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, substituted C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, and substituted C₆₋₁₀ aryl;    -   R⁷ and R⁸ are independently chosen from hydrogen, C₁₋₆ alkyl,        and substituted C₁₋₆ alkyl; and    -   R⁹ is chosen from C₁₋₆ alkyl and substituted C₁₋₆ alkyl;    -   wherein each substituent group is independently chosen from        halogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹,        —OR¹¹, —C(O)R¹¹, —COOR¹¹, and —NR¹¹ ₂ wherein each R¹¹ is        independently chosen from hydrogen and C₁₋₄ alkyl.

Useful examples of a compound of Formula (II) include:ethoxycarbonyloxyethyl methyl(2E)but-2-ene-1,4-dioate;methyl(methylethoxycarbonyloxy)ethyl(2E)but-2-ene-1,4-dioate;(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-dioate; and apharmaceutically acceptable salt of any of the foregoing.

Additional useful examples of a compound of Formula (II) include:methyl(2-methylpropanoyloxy)ethyl(2E)but-2-ene-1,4-dioate; methylphenylcarbonyloxyethyl(2E)but-2-ene-1,4-dioate;cyclohexylcarbonyloxybutyl methyl(2E)but-2-ene-1,4-dioate;[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethylmethyl(2E)but-2-ene-1,4-dioate; methyl2-methyl-1-phenylcarbonyloxypropyl(2E)but-2-ene-1,4-dioate; and apharmaceutically acceptable salt of any of the foregoing.

Useful examples of a compound of Formula (II) also include:ethoxycarbonyloxyethyl methyl(2E)but-2-ene-1,4-dioate;methyl(methylethoxycarbonyloxy)ethyl(2E)but-2-ene-1,4-dioate;methyl(2-methylpropanoyloxy)ethyl(2E)but-2-ene-1,4-dioate; methylphenylcarbonyloxyethyl(2E)but-2-ene-1,4-dioate;cyclohexylcarbonyloxybutyl methyl(2E)but-2-ene-1,4-dioate;[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethylmethyl(2E)but-2-ene-1,4-dioate; (cyclohexyloxycarbonyloxy)ethylmethyl(2E)but-2-ene-1,4-dioate; methyl2-methyl-1-phenylcarbonyloxypropyl(2E)but-2-ene-1,4-dioate;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoic acid, 2,2,2-trifluoroacetic acid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoicacid, 2,2,2-trifluoroacetic acid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoicacid, 2,2,2-trifluoroacetic acid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoicacid, 2,2,2-trifluoroacetic acid;3-{[(2E)-3-(methoxycarbonyl)prop-2enoyloxy]ethoxycarbonyloxy}(2S)-2-aminopropanoicacid, chloride; and a pharmaceutically acceptable salt of any of theforegoing.

Compounds that can be metabolized into MMF in vivo also includecompounds of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R² is C₁-C₁₀ alkyl, C₅-C₁₅ aryl, hydroxyl, —O—C₁-C₁₀ alkyl, or        —O—C₅-C₁₅ aryl; each of R³, R⁴, and R⁵, independently, is C₁-C₁₀        alkyl, C₅-C₁₅ aryl, hydroxyl, —O—C₁-C₁₀ alkyl, —O—C₅-C₁₅ aryl,        or

-   -   wherein R′ is C₁-C₂₄ alkyl or C₅-C₅₀ aryl; each of which can be        optionally substituted; and    -   each of m, n, and r, independently, is 0-4;    -   provided that at least one of R³, R⁴, and R⁵ is

Useful examples of a compound of formula (III) include(dimethylsilanediyl)dimethyl difumarate; methyl((trimethoxysilyl)methyl) fumarate; methyl ((trihydroxysilyl)methyl)fumarate; trimethyl (methylsilanetriyl) trifumarate; and apharmaceutically acceptable salt of any of the foregoing.

Compounds that can be metabolized into MMF in vivo also includecompounds of Formula (IV):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of, independently, R² and R³, is C₁-C₁₀ alkyl or C₅-C₁₅        aryl.    -   R² and R³ can be the same or different, can be optionally        substituted, and independently can be selected from the group        consisting of C₁-C₁₀ alkyl or C₅-C₁₅ aryl.

Compound that can be metabolized into MMF in vivo also include compoundsof Formula (V):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is C₁-C₂₄ alkyl or C₅-C₅₀ aryl;    -   each of R², R³, and R⁵, independently, is hydroxyl, C₁-C₁₀        alkyl, C₅-C₁₅ aryl, —O—C₁-C₁₀ alkyl, or —O—C₅-C₁₅ aryl; and    -   n is 1 or 2.

Additional compounds that can be metabolized into MMF in vivo includecompounds of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is C₁-C₂₄ alkyl or C₅-C₅₀ aryl; and

R² is C₁-C₁₀ alkyl.

As used herein, the term “fumarate agent” refers to MMF, a compound thatcan be metabolized into MMF in vivo (e.g., DMF), or a pharmaceuticallyacceptable salt thereof or combinations thereof, or deuterated analoguesthereof. In some embodiments, the fumarate agent can include more thanone compound, for example, a combination of MMF and DMF. In someembodiments, the fumarate agent is a single compound, e.g., DMF.

Useful examples of deuterated analogs include compounds of formula(VII): a compound of formula (I)

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   each of R¹ and R², independently, is hydrogen, deuterium,        deuterated methyl, deuterated ethyl, C₁₋₆ aliphatic, phenyl, 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring, 3-7 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or a        5-6 membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, and        each of R³ and R⁴, independently, is hydrogen or deuterium,        provided that the compound of formula (VII) contains at least        one deuterium atom and that R¹ and R² are not hydrogen at the        same time.

Useful examples of compounds of formula (VII) include (²H₆)dimethylfumaric acid ester, (²H₃)methyl fumaric acid ester, (²H₃)dimethylfumaric acid ester, dimethyl fumaric(2,3-²H₂) acid ester, methylfumaric(2,3-²H₂) acid ester, ethyl fumaric(2,3-²H₂) acid ester,(²H₃)methyl fumaric(2,3-²H₂) acid ester, (²H₆)dimethyl fumaric(2,3-²H₂)acid ester, methyl (2-morpholino-2-oxoethyl) fumaric(2,3-²H₂) acidester, methyl (4-morpholino-1-butyl) fumaric(2,3-²H₂) acid ester,2-(benzoyloxy)ethyl methyl fumaric(2,3-²H₂) acid ester,2-(benzoyloxy)ethyl (²H₃)methyl fumaric acid ester,(S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl methyl fumaric(2,3-²H₂) acidester, or (S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl (²H₃)methylfumaric acid ester.

4.3 Method 1. Treating a Subject Who May Receive a Vaccine

4.3.1 Method 1a.

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof;    -   (b) administering a vaccine to the subject; and    -   (c) administering to the subject a second dose of the        pharmaceutical composition for a second dosing period, wherein        the second dosing period is after the first dosing period. In        some embodiments, the disease or disorder is MS. In some        embodiments, the second dose is about 0 to about 480 mg fumarate        agent.

4.3.2 Method 1b.

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof, and wherein the subject        receives a vaccine;    -   (b) determining an immune response of the subject to the vaccine        before the end of the first dosing period; and    -   (c) adjusting the first dose to a second dose of the        pharmaceutical composition, which includes stopping        administration of the pharmaceutical composition (i.e., the        second dose can be about 0 to about 480 mg fumarate agent),        based on the immune response determined in step (b).

4.3.3 Method 1c.

In some embodiments, the invention provides a method of treating orpreventing a disease or disorder (e.g., MS) in a subject in needthereof, comprising

-   -   (a) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof, and wherein the subject        receives a vaccine;    -   (b) determining an immune response of the subject to the vaccine        before the end of the first dosing period; and    -   (c) administering to the subject a second dose of the        pharmaceutical composition for a second dosing period. In some        embodiments, the second dose is equal to or less than the first        dose.

4.3.4 Method 1d.

In some embodiments, the invention provides a method of treating orpreventing multiple sclerosis in a subject in need thereof, comprising

-   -   (a) determining a subject's baseline lymphocyte count prior to        treatment;    -   (b) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof;    -   (c) determining a subject's total lymphocyte count after the        first dosing period; and    -   (d) if the lymphocyte count after the first dosing period is 90%        of the baseline lymphocyte count or lower, do not administer        tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin        vaccine, pneumovax-23 vaccine, or any combinations thereof.

4.3.5 Method 1e.

In some embodiments, the invention provides a method of treatingmultiple sclerosis in a human subject in need thereof comprising

-   -   (a) administering a therapeutically effective amount of dimethyl        fumarate to the subject; and    -   (b) administering a vaccine to the subject.

In one embodiment, the therapeutically effective amount of dimethylfumarate is a maintenance dose that is repeatedly administered over atleast a period of time, and said step (b) of administering said vaccineis during said period of time.

The period of time can be, for example, for at least one, two, three,four, five, six, or seven days, or for at least one, two, three, or fourweeks, or for at least one, two, three, four, five, six, seven, eight,nine, ten, eleven, twelve months, or longer. In one embodiment, theperiod of time is 1 week. In another embodiment, the period of time is 6months. In a specific embodiment, the maintenance dose is administeredafter a time period during which the administered dosage is lower thanthe maintenance dose. For example, administration of a maintenance doseof 240 mg dimethyl fumarate administered orally twice daily can beimmediately preceded by a time period of uptitration consisting oforally administered 120 mg dimethyl fumarate twice daily for 7 days. Asanother example, administration of a maintenance dose of 240 mg dimethylfumarate administered orally twice daily can be immediately preceded bya time period of uptitration consisting of orally administering astarting dose of 120 mg dimethyl fumarate daily for 2 weeks, followed by120 mg dimethyl fumarate twice daily for 2 weeks, followed by 360 mgdimethyl fumarate daily for 2 weeks; wherein the 360 mg dimethylfumarate daily is 240 mg dimethyl fumarate in the morning and 120 mgdimethyl fumarate in the evening.

In one embodiment, the maintenance dose is orally administered 480 mgdimethyl fumarate daily. In a specific embodiment, the maintenance doseis orally administered 240 mg dimethyl fumarate twice daily.

In one embodiment, the immune response to said vaccine is decreased insaid subject relative to the immune response in the absence of said step(a) of administering a therapeutically effective amount of dimethylfumarate.

In one embodiment, the multiple sclerosis is a relapsing form ofmultiple sclerosis.

In one embodiment, the multiple sclerosis is relapsing-remittingmultiple sclerosis

4.3.6 Diseases and Disorders

Suitable diseases and disorders that can be treated by the fumarateagent are known in the art, which include any diseases or disorderswhere administering DMF is helpful.

In some embodiments, the disease or disorder where administering DMF ishelpful is

-   -   (1) an autoimmune disease selected from the group consisting of        polyarthritis, rheumatoid arthritis, multiple sclerosis,        graft-versus-host reactions, juvenile-onset diabetes,        Hashimoto's thyroiditis, Grave's disease, systemic Lupus        erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and        chronic active (=lupoid) hepatitis, psoriasis, psoriatic        arthritis, neurodermatitis and enteritis regionalis Crohn;    -   (2) a mitochondrial disease selected from the group consisting        of Parkinson syndrome, Alzheimer's disease, Chorea Huntington        disease, retinopathia pigmentosa or forms of mitochondrial        encephalomyopathy;    -   (3) a NF-kappaB mediated diseases selected from the group        consisting of progressive systemic sclerodermia, osteochondritis        syphilitica (Wegener's disease), cutis marmorata (livedo        reticularis), Behcet disease, panarteriitis, colitis ulcerosa,        vasculitis, osteoarthritis, gout, artenosclerosis, Reiter's        disease, pulmonary granulomatosis, types of encephalitis,        endotoxic shock (septic-toxic shock), sepsis, pneumonia,        encephalomyelitis, anorexia nervosa, hepatitis (acute hepatitis,        chronic hepatitis, toxic hepatitis, alcohol-induced hepatitis,        viral hepatitis, jaundice, liver insufficiency and        cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial        nephritis, post-angioplastic restenosis, reperfusion syndrome,        cytomegaloviral retinopathy, adenoviral diseases such as        adenoviral colds, adenoviral pharyngoconjunctival fever and        adenoviral ophthalmia, AIDS, Guillain-Barré syndrome,        post-herpetic or post-zoster neuralgia, inflammatory        demyelinising polyneuropathy, mononeuropathia multiplex,        mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV        (Epstein-Barr virus) infection, cardiac remodeling, interstitial        cystitis, diabetes mellitus type II, human tumour        radiosensitisation, multi-resistance of malignant cells to        chemotherapeutic agents (multidrug resistance in chemotherapy),        granuloma annulare and cancers such as mamma carcinoma, colon        carcinoma, melanoma, primary liver cell carcinoma,        adenocarcinoma, kaposi's sarcoma, prostate carcinoma, leukaemia        such as acute myeloid leukaemia, multiple myeloma        (plasmocytoma), Burkitt lymphoma and Castleman tumour;    -   (4) a cardiovascular disease selected from the group consisting        of cardiac insufficiency, myocardial infarct, angina pectoris        and combinations thereof;    -   (5) a respiratory disease selected from the group consisting of        asthma, chronic obstructive pulmonary diseases, PDGF induced        thymidine uptake of bronchial smooth muscle cells, bronchial        smooth muscle cell proliferation, and combinations thereof;    -   (6) a neurodegeneration or neuroinflammation selected from the        group consisting of Adrenal Leukodystrophy (ALD), Alcoholism,        Alexander's disease, Alper's disease, Alzheimer's disease,        Amyotrophic lateral sclerosis (Lou Gehrig's Disease), Ataxia        telangiectasia, Batten disease (also known as        Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform        encephalopathy (BSE), Canavan disease, Cerebral palsy, Cockayne        syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease,        Familial Fatal Insomnia, Frontotemporal lobar degeneration,        Huntington's disease, HIV-associated dementia, Kennedy's        disease, Krabbe's disease, Lewy body dementia, Neuroborreliosis,        Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple        System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick        disease, Parkinson's disease, Pelizaeus-Merzbacher Disease,        Pick's disease, Primary lateral sclerosis, Prion diseases,        Progressive Supranuclear Palsy, Refsum's disease, Sandhoff        disease, Schilder's disease, Subacute combined degeneration of        spinal cord secondary to Pernicious Anaemia,        Spielmeyer-Vogt-Sjögren-Batten disease (also known as Batten        disease), Spinocerebellar ataxia, Spinal muscular atrophy,        Steele-Richardson-Olszewski disease, Tabes dorsalis, Toxic        encephalopathy, LHON (Leber's Hereditary optic neuropathy),        MELAS (Mitochondrial Enccphalomyopathy; Lactic Acidosis;        Stroke), MERRF (Myoclonic Epilepsy; Ragged Red Fibers), PEO        (Progressive External Opthalmoplegia), Leigh's Syndrome, MNGIE        (Myopathy and external ophthalmoplegia; Neuropathy;        Gastro-Intestinal; Encephalopathy), Kearns-Sayre Syndrome (KSS),        NARP, Hereditary Spastic Paraparesis, Mitochondrial myopathy,        and Friedreich Ataxia; or    -   (7) a demyelinating neurological disorder selected from the        group consisting of optic neuritis, acute inflammatory        demyelinating polyneuropathy (AIDP), chronic inflammatory        demyelinating polyneuropathy (CIDP), acute transverse myelitis,        progressive multifocal leucoencephalopathy (PML), acute        disseminated encephalomyelitis (ADEM) or other hereditary        disorders (e.g., leukodystrophies, Leber's optic atrophy, and        Charcot-Marie-Tooth disease).

In some embodiments, the disease or disorder where administering DMF ishelpful is a neutrophil mediated disease or disorder (e.g., an allergicdisease or disorder, an inflammatory disease or disorder, an autoimmunedisease or disorder, or a tumor).

Non-limiting examples of autoimmune diseases or disorders includeautoimmune Addison's disease, autoimmune hemolytic anemia, autoimmunehepatitis, autoimmune inner ear disease, autoimmune lymphoproliferativesyndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), orautoimmune skin blistering diseases (AIBD).

Non-limiting examples of autoimmune skin blistering diseases includeepidermolysis bullosa acquistita (EBA), pemphigoid disease (e.g.,bullous pemphigoid, mucous membrane pcmphigoid, or pcmphigoidgcstationis), IgA-mediated bullous dermatoses (e.g., DermatitisHerpetiformis or Linear TgA Bullous Dermatosis), and pemphigus disease(e.g., IgA Pemphigus).

Non-limiting neutrophil mediated diseases or disorders also include aninflammatory skin or subcuteneous disease selected from the groupconsisting of Pyoderma Gangrenosum, Erosive Pustular Dermatosis of theScalp, Sweet's Syndrome, Bowel-associated Dermatosis-arthritis Syndrome,Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis,Keratoderma Blenorrhagicum, Sneddon-Wilkinson Disease, AmicrobialPustulosis of the Folds, Infantile Acropustulosis, Transient NeonatalPustulosis, Neutrophilic Eccrine Hidradenitis, Rheumatoid NeutrophilicDermatitis, Neutrophilic Urticaria, Still's Disease, ErythemaMarginatum, Unclassified Periodic Fever Syndromes/AutoinflammatorySyndromes, Bullous Systemic Lupus Erythematosus, and NeutrophilicDermatosis of the Dorsal Hands (Pustular Vasculitis);

Non-limiting neutrophil mediated diseases or disorders also include:

-   -   a) an allergic condition selected from the group consisting of        anaphylaxis, allergic rhinitis and allergic asthma;    -   b) neutrophil mediated respiratory disease selected from the        group consisting of lung cancer, severe asphyxic episodes of        asthma, acute lung injury, and Acute Respiratory Distress        Syndrome;    -   c) an acute tissue injury selected from the group consisting of        acute kidney injury, ischemia reperfusion injury, sepsis, and        septicemia with multiorgan failure;    -   d) an inflammatory bowel disease selected from the group        consisting of ulcerative colitis, Crohn's disease, and        inderteminate colitis; and    -   e) sickle cell crisis or acute chest syndrome.

In some embodiments, the disease or disorder where administering DMF ishelpful is a disease or disorder that is associated with aberrantPI3K/AKT signaling, including cancer, chronic inflammation and allergy,neurodegenerative disease, cardiovascular disease and metabolicdiseases. Non-limiting examples of disease or disorders that areassociated with aberrant PI3K/AKT signaling include all forms of cancer,precancerous lesions, cardiovascular disease, rheumatologic disease,pulmonary disease, dermatologic disease, gynecological diseases,vascular disease, neurologic disease, and infectious disease includingbacterial, viral, retroviral, and parasitic diseases. In someembodiments, the disease or disorder to be treated is cancer.Non-limiting examples of cancer include breast cancer, lung cancer,ovarian cancer, uterine cancer, brain cancer, sarcoma, melanoma,leukemia, lymphoma, colorectal cancer, prostate cancer, and livercancer. In some embodiments, the disease or disorder to be treated isrheumatologic disease, e.g., rheumatoid arthritis or osteoarthritis. Insome embodiments, the disease or disorder to be treated is pulmonarydisease, e.g., allergic rhinitis, chronic obstructive pulmonary disease(COPD).

In some embodiments, the disease or disorder where administering DMF ishelpful is a disease or disorder that is associated with aberrant p38MAPK signaling. Non-limiting examples of such diseases include COPD(including chronic bronchitis and emphysema), asthma, pediatric asthma,cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergicrhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis,allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis,inflamed joints secondary to rheumatoid arthritis or osteoarthritis,rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growthand metastasis of tumours including non-small cell lung carcinoma,breast carcinoma, gastric carcinoma, colorectal carcinomas and malignantmelanoma.

In some embodiments, the disease or disorder is a neurological diseaseor disorder. In some embodiments, the neurological disease or disorderis an autoimmune disease. In some embodiments, the neurological diseaseor disorder is a demyelinating disease or disorder.

In some embodiments, the neurological disease or disorder is selectedfrom the group consisting of multiple sclerosis (MS), Huntington'sdisease, Alzheimer's disease, Parkinson's disease, optic neuritis, Devicdisease, transverse myelitis, acute disseminated encephalomyelitis,adrenoleukodystrophy and adrenomyeloneuropathy, acute inflammatorydemyelinating polyneuropathy (AIDP), chronic inflammatory demyelinatingpolyneuropathy (CIDP), acute transverse myelitis, progressive multifocalleucoencephalopathy (PML), acute disseminated encephalomyelitis (ADEM)and other hereditary disorders, such as leukodystrophies, Leber's opticatrophy, and Charcot-Marie-Tooth disease.

In some embodiments, the neurological disease or disorder is multiplesclerosis. In some embodiments, the MS is relapsing remitting MS,secondary progressive MS, primary progressive MS, progressive relapsingMS, or clinically isolated syndrome (CIS). In some embodiments, theneurological disease or disorder is a relapsing form of MS.

4.3.7 Vaccination Schedule

Various vaccination schedules are suitable for the methods describedherein. In some embodiments, the subject receives the vaccine during thefirst dosing period. For example, the subject can receive the vaccinefrom one week to 24 weeks (e.g., 1 week, 2 weeks, 4 weeks, 8 weeks, 12weeks, 16 weeks, 20 weeks, 24 weeks, or any ranges thereof) before thestart of the first dosing period. In some embodiments, the subjectreceives the vaccine more than 24 weeks (e.g., more than 48 weeks, morethan 96 weeks, or more than 5 years) before the start of the firstdosing period. In some embodiments, the subject receives the vaccineduring the first dosing period, for example, from 1 week to 48 weeks(e.g., 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks,24 weeks, 36 weeks, 48 weeks, or any ranges thereof) after the start ofthe first dosing period. In some embodiments, the subject receives thevaccine from 1 week to 48 weeks (e.g., 1 week, 2 weeks, 4 weeks, 8weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 36 weeks, 48 weeks, orany ranges thereof) before the end of the first dosing period. In someembodiments, the subject receives at least one vaccine (e.g., 2vaccines, 3 vaccines, 4 vaccines, or more than 4 vaccines) during thefirst dosing period. In some embodiments, each vaccine contains either asingle antigen or multiple antigens.

In some embodiments, the first dosing period lasts from 1 month to 2years (e.g., 1 month, 3 months, 6 months, 1 year, 2 year, or any rangesthereof). In some embodiments, the first dosing period is more than 2years (e.g., more than 3 years, or more than 5 years). In someembodiments, the first dosing period lasts until the vaccine isadministered to the subject.

In some embodiments, the second dosing period lasts from 1 week to 2years (e.g., 1 week, 1 month, 3 months, 6 months, 1 year, 2 year, or anyranges thereof). In some embodiments, the second dosing period is morethan 2 years (e.g., more than 3 years, more than 5 years, or for life).In some embodiments, the second dosing period lasts less than 1 week(e.g., 1, 2, 3, 4, 5, or 6 days). In some embodiments, the second dosingperiod is initiated within a week of (e.g., 1 day, 2 days, 3 days, 4days, 5 days, 6 days, or 7 days after) the end of the first dosingperiod. In some embodiments, the second dosing period is initiated 1week to 48 weeks (e.g., 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16weeks, 20 weeks, 24 weeks, 36 weeks, 48 weeks, or any ranges thereof)after the end of the first dosing period. In some embodiments, thesecond dosing period is initiated on the same day on which the firstdosing period ends. In other embodiments, the second dosing period isinitiated on the same day as the subject receives a vaccine.

4.3.8 First and Second Doses

Various amounts of the fumarate agent can be used for the first andsecond doses in the methods described herein. In some embodiments, thefirst or second dose of the pharmaceutical composition contains atherapeutically effective amount of the fumarate agent. In someembodiments, the fumarate agent comprises MMF, DMF, or a combinationthereof. In some embodiments, the fumarate agent comprises DMF. In someembodiments, the only active ingredient in the pharmaceuticalcomposition is DMF. In a preferred embodiment, the pharmaceuticalcomposition is Tecfidera® which is a controlled-release microtabletformulation containing 240 mg of DMF per capsule and the first or seconddose of the pharmaceutical composition is effected by administering aTecfidera® capsule to the subject twice daily or three times daily. Inone embodiment, the first or second dose of the pharmaceuticalcomposition is effected by administering a Tecfidera® capsule to thesubject twice daily for a total daily dose of 480 mg.

In some embodiments, the second dose is no greater than the first dose.In some embodiments, the second dose is the same as the first dose. Insome embodiments, the second dose is about 5% to about 95% (e.g., about10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%,about 80%, about 90%, or any ranges thereof) of the first dose. Forexample, the first dose can be a daily amount of about 480 mg of DMF,e.g., effected by a BID dosing, and the second dose can be 50% of thefirst dose, which is a daily amount of about 240 mg of DMF, which canalso be effected by a BID dosing. In some embodiments, the second doseis less than 50% of the first dose. In some embodiments, the second doseis a daily amount of about 0 to about 480 mg fumarate agent. In someembodiments, the second dose is a daily amount of about 120 mg, about240 mg, about 360 mg, or about 480 mg fumarate agent administered to thesubject in 1, 2, or 3 (e.g., equal) doses. In some embodiments, thesecond dose is 0 mg fumarate agent.

In some embodiments, the subject is administered the same amount offumarate agent as in the first dosing period after the second dosingperiod.

In some embodiments, the methods described herein further comprisesadministering a titration dose of the pharmaceutical composition priorto the first and/or second dosing periods. In some embodiments, thetitration dose is administered to the subject for at least 7 days priorto beginning the first or second dosing period. In some embodiments, thefumarate agent is DMF and the titration dose is a daily dose of about240 mg DMF administered BID for 7 consecutive days. In some embodiments,the fumarate agent is DMF and the titration dose is a daily dose of 360mg DMF administered three times a day for 7 consecutive days.

The pharmaceutical composition can be in different forms. Non-limitingexamples include pills, tablets, microtablets, pellets, powders,granules, micropellets, capsules (e.g., containing microtablets), liquidformulations for oral administration, and the form of dietarysupplements. Methods for preparing pharmaceutical compositions in theseforms are known in the art. Suitable pharmaceutically acceptableexcipients for preparing the pharmaceutical compositions are also knownin the art, for example, binders, fillers, disintegrants, glidants,lubricants, diluents, plasticizers, etc. as described in Remington'sPharmaceutical Science, 18^(th) Edition, 1990, Mack Publishing Company,Easton, Pa. (“Remington's”).

In some embodiments, the pharmaceutical composition is in the form of acapsule (such as a soft or hard gelatine capsule) containing DMF in theform of microtablets or micropellets (e.g., enteric-coated microtabletsor micropellets). Suitable microtablets or micropellets are, withoutlimitation, those having a mean diameter of 5,000 microns or less (e.g.,4,000 microns or less, 3,000 microns or less, 2,000 microns or less,1,000 microns or less, or 500 microns or less) exclusive of any optionalcoating applied to the microtablets or micropellets. In someembodiments, the pharmaceutical composition is in the form of a capsulecontaining a pharmaceutical preparation consisting essentially of 60-240mg (e.g., 120 mg, or 240 mg) of DMF in the form of enteric-coatedmicrotablets. In some embodiments, the mean diameter of suchmicrotablets is 1,000-5,000 microns, e.g., 1,000-3,000 microns or 2,000microns. Methods for preparing microtablets or micropellets (e.g.,enteric-coated microtablets or micropellets) comprising DMF are known inthe art, for example, as described in U.S. Pat. No. 6,509,376 andincorporated by reference in its entirety herein.

The pharmaceutical composition suitable for the methods described hereininclude without limitation those formulated as an enterically coatedimmediate release dosage form, or a controlled release dosage form(e.g., a delayed release dosage form, a sustained release dosage form, apulsatile release dosage form). In some embodiments, the controlledrelease dosage form is a gastric retentive dosage form. In someembodiments, the pharmaceutical composition is formulated as anenterically coated immediate release dosage form. In some embodiments,the pharmaceutical composition is formulated as a delayed release dosageform. The fumarate agent (e.g., DMF, MMF, or a combination thereof) canbe administered in the form of a sustained or controlled releasepharmaceutical formulation. Such formulation can be prepared by varioustechnologies by a skilled person in the art. For example, theformulation can contain the therapeutic compound, a rate-controllingpolymer (i.e., a material controlling the rate at which the therapeuticcompound is released from the dosage form) and optionally otherexcipients. Some examples of rate-controlling polymers are hydroxy alkylcellulose, hydroxypropyl alkyl cellulose (e.g., hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, hydroxypropyl isopropylcellulose, hydroxypropyl butyl cellulose and hydroxypropyl hexylcellulose), poly(ethylene)oxide, alkyl cellulose (e.g., ethyl celluloseand methyl cellulose), carboxymethyl cellulose, hydrophilic cellulosederivatives, and polyethylene glycol, compositions, e.g., thosedescribed in WO 2006/037342, incorporated herein by reference.

The pharmaceutical composition can be administered with or without food.In some embodiments, the pharmaceutical composition comprising thefumarate agent (e.g., DMF) is administered at least one hour before orat least one hour after food is consumed by the subject. In someembodiments, the pharmaceutical composition comprising the fumarateagent (e.g., DMF) is administered with food, for example, to reduceflushing.

In some embodiments, the neurological disorder is multiple sclerosis,wherein the first or second dose of the fumarate agent (e.g., DMF) is anamount that is effective in treating or preventing of multiplesclerosis, for example, in a subject who receives a vaccine before orduring the first dosing period. For example, for DMF or MMF, the firstor second dose can be a therapeutically effective amount range fromabout 1 mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20mg/kg or from about 2.5 mg/kg to about 15 mg/kg). Effective doses willvary, as recognized by those skilled in the art, dependent on route ofadministration, excipient usage, and the possibility of co-usage withother therapeutic treatments including use of other therapeutic agents.

In some embodiments, the first or second dose of DMF or MMF can be atherapeutically effective dose. In some embodiments, the therapeuticallyeffective dose is a daily dose of from about 20 mg to about 1 g, forexample, from about 100 mg to about 800 mg (e.g., from about 120 mg toabout 720 mg, from about 240 mg to about 720 mg; or from about 480 mg toabout 720 mg; or about 720 mg). The therapeutically effective dose ofDMF or MMF can also be, for example, a daily dose of about 60 mg, about80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240mg, about 320 mg, about 360 mg, about 400 mg, about 480 mg, about 600mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg of DMF orMMF, or any ranges thereof. The dosages can be administered one or moretimes per day. For example, a 720 mg daily dose can be administered allat once or in separate administrations of 2, 3, 4, 5 or 6 (e.g., equal)doses. A 480 mg daily dose can be administered all at once or inseparate administrations of 2, 3, 4, 5 or 6 (e.g., equal) doses. In someembodiments, the therapeutically effective dose of DMF or MMF is about480 mg per day, effected by two equal, separate administrations, i.e.,240 mg per administration, at about 6 to about 12 hours apart in a day.In some embodiments, the therapeutically effective dose of DMF or MMF isabout 720 mg per day, effected by three equal, separate administrations,i.e., 240 mg per administration, at about 4 to about 8 hours apart in aday. In some embodiments, the therapeutically effective dose of DMF orMMF is 300 mg to 1000 mg per day. In some embodiments, thetherapeutically effective dose of DMF or MMF is 300 mg to 1000 mg perday delivered once daily. In some embodiments, the therapeuticallyeffective dose of DMF or MMF is about 720 mg per day delivered oncedaily. In some embodiments, the therapeutically effective dose of DMF orMMF is about 480 mg per day delivered once daily.

In some embodiments, the first or second dose is administered to thesubject by orally administering a dosage form that provides a totalamount of about 60 mg to about 1000 mg of DMF. The dosage form can, forexample, contain a total amount of DMF effective for treatment orprophylaxis of multiple sclerosis. The effective amount can range, butis not limited to, a total amount of about 60 mg to about 800 mg DMF,about 60 mg to about 720 mg DMF, 60 mg to about 500 mg DMF, about 60 mgto about 480 mg DMF, about 60 mg to about 420 mg DMF, about 60 mg toabout 360 mg DMF, about 60 mg to about 240 mg DMF, about 60 mg to about220 mg DMF, about 60 mg to about 200 mg DMF, about 60 mg to about 180 mgDMF, about 60 mg to about 160 mg DMF, about 60 mg to about 140 mg DMF,about 60 mg to about 120 mg DMF, about 60 mg to about 100 mg DMF, about60 mg to about 80 mg DMF, about 80 mg to about 480 mg DMF, about 100 mgto about 480 mg DMF, about 120 mg to about 480 mg DMF, about 140 mg toabout 480 mg DMF, about 160 mg to about 480 mg DMF, about 180 mg toabout 480 mg DMF, about 200 mg to about 480 mg DMF, about 220 mg toabout 480 mg DMF, about 240 mg to about 480 mg DMF, about 300 mg toabout 480 mg DMF, about 360 mg to about 480 mg DMF, about 400 mg toabout 480 mg DMF, about 450 mg to about 500 mg DMF, about 480 mg toabout 500 mg DMF, about 80 to about 400 mg DMF, about 100 to about 300mg DMF, about 120 to about 180 mg DMF, or about 140 mg to about 160 mgDMF.

The dosage form can contain, but is not limited to, a total amount ofDMF of about 60 mg DMF, about 80 mg DMF, about 100 mg DMF, about 120 mgDMF, about 140 mg DMF, about 160 mg DMF, about 180 mg DMF, about 200 mgDMF, about 220 mg DMF, about 240 mg DMF, about 260 mg DMF, about 280 mgDMF, about 300 mg DMF, about 320 mg DMF, about 340 mg DMF, about 360 mgDMF, about 380 mg DMF, about 400 mg DMF, about 420 mg DMF, about 450 mgDMF, about 480 mg DMF, or about 500 mg DMF. In some embodiments, DMF isthe only active ingredient in the dosage form.

In some embodiments, the fumarate agent is a compound that can bemetabolized into MMF in vivo. And the first or second dose of thefumarate agent includes any amount of the compound that is equivalent tothe amount of DMF or MMF described herein based on fumaric acid content.

In a healthy volunteer study, administration of 325 mg non-entericcoated aspirin 30 minutes prior to DMF dosing is found to reduce theoccurrence and severity of flushing in the participating subjects.Subjects receiving a vaccine who experience flushing may be administered(e.g., 30 min. prior to DMF dosing) about 325 mg of aspirin to reduceflushing. Some patients who experience flushing with gastrointestinalside effects may reduce the dose to 120 mg DMF BID temporarily. Within amonth, the effective dose of 240 mg DMF BID should be resumed.

In one embodiment, the method described herein further comprisesadministering to the subject one or more non-steroidal anti-inflammatorydrugs (e.g., aspirin) before (for example, 10 minutes to an hour, e.g.,30 minutes before) administering the first or second dose of thepharmaceutical composition comprising the fumarate agent. In oneembodiment, the subject administered the pharmaceutical compositioncomprising the fumarate agent takes the one or more non-steroidalanti-inflammatory drugs (e.g., aspirin) to reduce flushing. In anotherembodiment, the one or more non-steroidal anti-inflammatory drugs isselected from a group consisting of aspirin, ibuprofen, naproxen,ketoprofen, celecoxib, and combinations thereof. The one or morenon-steroidal anti-inflammatory drugs can be administered in an amountof about 50 mg to about 500 mg before taking the dosage form describedabove. In one embodiment, a patient takes 325 mg aspirin before takingthe pharmaceutical composition comprising the fumarate agent.

4.3.9 Immune Responses to the Vaccine

In any of the embodiments described herein, the subject can receive anytype of vaccine (e.g., live or inactive vaccines). In a specificembodiment, the vaccine is a subunit vaccine. In some embodiments, thevaccine induces a T cell-dependent immune response (e.g., a Tcell-dependent anamnestic humoral response, or a T cell-dependentprimary response). In some embodiments, the vaccine induces a Tcell-dependent anamnestic humoral immune response. In other embodiments,the vaccine induces a T cell-dependent neoantigen immune response.

In some embodiments, the vaccine induces an immune response against avirus, which can be, but is not limited to, adenovirus, arbovirus,coxsackievirus, cytomegalovirus, dengue virus, echinovirus, ebola virus,echovirus, enterovirus, hepatitis type A, hepatitis type B, hepatitistype C, herpes simplex virus type I (HSV-I), herpes simplex virus typeII (HSV-II), human immunodeficiency virus type I (HIV-I), humanimmunodeficiency virus type II (HIV-II), hantavirus, influenza, measlesvirus, mumps virus, papillomavirus, papovavirus, polio virus,respiratory syncytial virus, rhinovirus, rinderpest, rotavirus, rubellavirus, SARS coronavirus or varicella. In some embodiments, the vaccineinduces an immune response against a bacterium of a genus, which can be,but is not limited to, Chlamydia, Clostridium, Corynebacterium,Legionella, Mycobacterium, Mycoplasma, Neisseria, Rickettsia, orStreptococcus. In a specific embodiment, the bacterium is Clostridiumtetani, Corynebacterium diphtheria, Neisseria meningitides, orStreptococcus pneumoniae. In some embodiments, the vaccine induces animmune response against a protozoan of a genus, which can be, but is notlimited to, Kokzidioa, Leishmania, or Trypanosoma.

In some embodiments, the vaccine induces a T cell-independent immuneresponse (e.g., a Type 1 or Type 2 T cell-independent immune response).In some embodiments, the subject receives one vaccine that induces a Tcell-dependent immune response and another vaccine that induces a Tcell-independent immune response. In some embodiments, the subjectreceives a vaccines that has been approved by the U.S. Food and DrugAdministration (FDA) or other corresponding foreign regulatoryauthorities. Non-limiting examples of FDA approved vaccines for useinclude those listed under the tradenames of Biothrax, BCG Vaccine, TICEBCG, Tripedia, Infanrix, DAPTACEL, Pediarix, KINRIX, Pentacel,PedvaxHIB, ActHIB, Hiberix, Comvax, Havrix, VAQTA, Twinrix, RecombivaxHB, Engerix-B, Gardasil, Cervarix, Afluria, FluLaval, FluMist, Fluarix,Fluvirin, Agriflu, Fluzone, Fluzone High-Dose and Fluzone Intradermal,Flucelvax, Flublok, FluMist Quadrivalent, Fluarix Quadrivalent, FluzoneQuadrivalent, FluLaval, Quadrivalent, Ixiaro, JE-Vax, M-M-Vax, M-M-R II,ProQuad, MENVEO, MenHibrix, Menactra, Menomune-A/C/Y/W-135, Pneumovax23, Prevnar, Prevnar 13, Poliovax, IPOL, Imovax, RabAvert, ROTARIX,RotaTeq, ACAM2000, DECAVAC, TENIVAC, Adacel, Boostrix, Vivotif, TYPHIMVi, Varivax, YF-Vax, and Zostavax. In some embodiments, the vaccine is atetanus diphtheria toxoids vaccine (e.g., TENIVAC). In some embodiments,the vaccine is a KLH vaccine. In some embodiments, the vaccine isPNEUMOVAX 23. In some embodiments, the vaccine is meningococcalpolysaccharide diphtheria conjugate vaccine, quadrivalent (i.e., MCV4;e.g., MENVEO, which is Meningococcal [Groups A, C, Y and W-135]Oligosaccharide Diphtheria CRM₁₉₇ Conjugate Vaccine). In someembodiments, the vaccine is selected from the group consisting oftetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine,pneumovax-23 vaccine, and any combinations thereof. In some embodiments,the vaccine is selected from the group consisting of tetanus diphtheriatoxoids vaccine, pneumovax-23 vaccine, and meningococcal polysaccharidediphtheria conjugate vaccine (quadrivalent). In some embodiments, thesubject receives more than one vaccine during the first dosing period.In one embodiment, the patient receives more than one vaccine on thesame day. Suitable doses, routes of administration, and immunizationschedules for the vaccine can be any of those according to a FDAapproved label for the vaccine.

Immune responses of a subject to a vaccine can be measured by any methodknown to those skilled in the art. In some embodiments, the step ofdetermining the immune response comprises obtaining serum antibody(e.g., IgG or IgM) levels in the subject induced by the vaccinepost-immunization (e.g., 4 weeks after immunization), obtaining theserum antibody (e.g., IgG or IgM) levels in the subjectpre-immunization, and comparing the serum antibody levels in the subjectpre- and post-immunization. Methods for measuring serum antibody levelsare known in the art. In some embodiments, the serum antibody level inthe subject increases less than 4-fold (e.g., less than 3-fold or lessthan 2-fold) from pre-immunization to 4 weeks after immunization. Insome embodiments, the serum antibody level in the subject increases atleast 2-fold (e.g., at least 4-fold or at least 10-fold) frompre-immunization to 4 weeks after immunization. In some embodiments, theserum antibody is IgG against tetanus diphtheria toxoids, keyhole limpethemocyanin, or pneumovax-23, and the serum IgG level in the subjectincreases less than 4-fold (e.g., less than 3-fold or less than 2-fold)from pre-vaccination to 4 weeks after vaccination. In some embodiments,the serum IgG level in the subject increases at least 2-fold (e.g., atleast 4-fold or at least 10-fold) from pre-immunization to 4 weeks afterimmunization.

In some embodiments, the immune response of the subject to the vaccineis characterized in that the serum antibody level in the subjectincreases at least 2-fold (e.g., at least 4-fold or at least 10-fold)from pre-immunization to 4 weeks after immunization, and the second doseis the same as the first dose. In some embodiments, the serum antibodyis IgG against tetanus diphtheria toxoids, keyhole limpet hemocyanin, orpneumovax-23.

In some embodiments, the first dose is a daily dose of about 480 mg orabout 720 mg of DMF divided into 1, 2, or 3 (e.g., equal) doses. In someembodiments, the second dose is a daily dose of about 120 mg, about 240mg, or about 360 mg divided into 1, 2, or 3 (e.g., equal) doses. In someembodiments, the second dose is 0 mg fumarate agent. In someembodiments, the subject is administered the same amount of fumarateagent as in the first dosing period after the second dosing period.

4.4 Method 2. Screening for Lower Risk Dose

In some embodiments, the invention also provides a method of treating orpreventing a disease or disorder (e.g., as described herein) in asubject who receives a vaccine, comprising screening a plurality ofdoses of a pharmaceutical composition comprising a fumarate agentselected from the group consisting of monomethyl fumarate, a compoundthat metabolizes into monomethyl fumarate in vivo, a deuterated analogthereof, a pharmaceutically acceptable salt thereof, and a combinationthereof, by

-   -   (1) identifying a first group of subjects and at least a second        group of subjects, wherein both the first and second groups of        subjects receive a vaccine, wherein the first group of subjects        is treated with a first dose of the pharmaceutical composition,        and the second group of subjects is treated with a second dose        of the pharmaceutical composition; and    -   (2) determining a lower risk dose. In some embodiments, the        method further comprises administering the lower risk dose of        the pharmaceutical composition to the subject.

Methods for determining a lower risk dose of the pharmaceuticalcomposition are known. In some embodiments, the lower risk dose isdetermined by comparing immune responses to the vaccine between thefirst and second groups of subjects, and the group of subjects treatedwith the lower risk dose have higher proportion of subjects with atleast 2-fold increase in scrum antibody levels induced by the vaccinefrom pre-vaccination to 4 weeks after vaccination. In some embodiments,the group of subjects treated with the lower risk dose have higherproportion of subjects having serum antibody levels induced by thevaccine not less than average serum antibody level observed in subjectsadministered with the vaccine but no fumarate agent at 4 weeks aftervaccination.

Methods for determining a lower risk dose can also include comparingadverse effects observed between the first and second groups ofsubjects. In some embodiments, the group of subjects treated with thelower risk dose have a lower rate of a particular adverse effect (e.g.,decreased incidence of headache, flushing, gastrointestinal event, orinfection).

In some embodiments, the invention provides a method of treating orpreventing multiple sclerosis in a subject in need thereof, comprising

-   -   (a) determining a subject's baseline lymphocyte count prior to        treatment;    -   (b) administering to the subject a first dose of a        pharmaceutical composition for a first dosing period, wherein        the pharmaceutical composition comprises a fumarate agent        selected from the group consisting of monomethyl fumarate, a        compound that metabolizes into monomethyl fumarate in vivo, a        deuterated analog thereof, a pharmaceutically acceptable salt        thereof, and a combination thereof;    -   (c) determining a subject's total lymphocyte count after the        first dosing period; and    -   (d) if the lymphocyte count after the first dosing period is 90%        of the baseline lymphocyte count or lower, do not administer        tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin        vaccine, pneumovax-23 vaccine, or any combinations thereof.

In some embodiments, the lymphocyte count after the first dosing periodis about 10% to about 90% of the baseline lymphocyte count. In someembodiments, the lymphocyte count is about 10% to about 80% of thebaseline lymphocyte count. In some embodiments, the lymphocyte count isabout 10% to about 70% of the baseline. In some embodiments, thelymphocyte count is about 10% to about 50% of the baseline. In someembodiments, the lymphocyte count after the first dosing period is about20% to about 90% of the baseline lymphocyte count. In some embodiments,the lymphocyte count is about 20% to about 80% of the baselinelymphocyte count. In some embodiments, the lymphocyte count is about 20%to about 70% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 20% to about 60% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 20% to about50% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 30% to about 90% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 30% to about80% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 30% to about 70% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 30% to about60% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 40% to about 90% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 40% to about80% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 40% to about 70% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 40% to about70% of the baseline lymphocyte count. In some embodiments, thelymphocyte count is about 40% to about 60% of the baseline lymphocytecount. In some embodiments, the lymphocyte count is about 40% to about50% of the baseline lymphocyte count. In some embodiments, thelymphocyte count after the first dosing period is about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,or about 90% of the baseline lymphocyte count.

Suitable fumarate agents, first and second doses of the pharmaceuticalcomposition, vaccines, methods for determining immune responses to thevaccines, and diseases or disorders can be those described herein forMethod 1.

The following examples are illustrative and do not limit the scope ofthe claimed embodiments.

5. EXAMPLES 5.1 Example 1: A Randomized, Open-Label Study to Assess theEffects of BG00012 on the Immune Response to Vaccination and onLymphocyte Subsets in Subjects with Relapsing Forms of MultipleSclerosis

5.1.1 Introduction

The primary objective of the study is to evaluate the effects of DMFadministered over approximately 6 months on immune responses tovaccination with tetanus diphtheria toxoids vaccine (Td) [Tcell-dependent anamnestic humoral response] and keyhole limpethemocyanin (KLH) [T cell-dependent neoantigen response] in subjects withrelapsing forms of MS.

Secondary objectives of this study in this study population are asfollows: (1) to evaluate the effects of DMF administered overapproximately 6 months on the immune response to vaccination withpneumovax-23 (PPSV23) [a mostly T cell-independent humoral response];(2) to evaluate the pharmacodynamic effects of DMF on lymphocytesubtypes over 1 year of treatment; (3) to evaluate the pharmacodynamiceffect of DMF on immunoglobulin levels over time; and (4) to evaluatethe safety and tolerability of DMF.

5.1.2 DMF and Vaccines for the Study

DMF is a drug product formulated as enteric-coated microtablets ingelatin capsules (blue and white) for oral administration. Each capsulecontains 120 mg DMF. Excipients for the manufacturing of theenteric-coated microtablets include microcrystalline cellulose,croscarmellose sodium, talc, colloidal anhydrous silica (colloidalsilicon dioxide), magnesium stearate, triethyl citrate, methacrylicacid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylatecopolymer, simethicone, sodium lauryl sulfate, and polysorbate 80.Excipients for the manufacturing of the capsule shell include gelatin,titanium dioxide, and indigotin.

Tetanus diphtheria toxoids vaccine (Td [Tenivac®]; Sanofi Pasteur,Swiftwater, Pa.) is indicated for active immunization for the preventionof tetanus and diphtheria. It is used in this study to assess theintegrity of a T cell-dependent anamnestic humoral response, as tetanustoxoid is an immunogen commonly administered to the general population.

Keyhole limpet hemocyanin (KLH) is used to test the integrity of a Tcell-dependent primary response, as it is a novel immunogen for mostindividuals. KLH is administered as Immucothel® (Biosyn Arzneimittel AG,Fellbach, Germany), a hemocyanin product derived from KLH, which isobtained from the sea snail giant keyhole limpet. Immucothel is approvedfor treatment of bladder cancer in several countries and is consideredan investigational agent in the US, where it is used in clinical studiesto produce an immune response.

Pneumovax® 23 (PPSV23; Merck & Co., Inc., Rahway, N.J., USA) is a23-valent carbohydrate antigen vaccine approved for the prophylaxis ofcommunity-acquired pneumonia. Pneumococcal polysaccharide antigens areable to activate B cells without T cell help, and thus are consideredtype 2 T cell independent antigens. However, they are also able toinduce an adaptive humoral immune response, due to a secondary signal ofB cell activation provided by other immune cells and with some T cellinvolvement. PPSV23 is therefore be used in this study to assess amostly T cell-independent humoral response.

5.1.3 Dosage Selection

The DMF dosage selected for this study (120 mg twice daily [BID] for thefirst week, 240 mg BID thereafter) is the approved DMF dosing regimen inpatients with relapsing forms of MS in the United States (US).

Td (0.5 mL) and PPSV23 (0.5 mL) doses selected for this study are thecurrent approved doses for these vaccines. KLH (1 mg) is thesubcutaneous (SC) injection dose based on Immucothel Investigator'sBrochure.

Subjects with relapsing forms of MS between the ages of 18 and 55 years,with a known history of tetanus immunization.

5.1.4 Inclusion/Exclusion Criteria

Exemplary eligibility criteria at randomization include: (1) Male andfemale subjects of childbearing potential will practice effectivecontraception during the study and be willing and able to continuecontraception for 30 days after their last dose of study treatment; (2)Aged 18 to 55 years old, inclusive, at the time of informed consent; (3)a confirmed diagnosis of a relapsing form of MS; and (4) a known historyof tetanus immunization.

Exemplary exclusion criteria at randomization include: (1) Tetanusvaccination given less than 2 years or more than 15 years prior toScreening, or an anti-tetanus IgG titer at Screening that is greaterthan one-half the upper limit of detection for the assay; (2)Pneumococcal vaccination within the 5 years prior to Screening; (3)Previous exposure to KLH or vaccines containing KLH components (e.g.,cancer vaccines); (4) Known hypersensitivity to KLH, PPSV23, ortetanus/diphtheria toxoids or any other administered vaccinations ortheir components (e.g., thimerosol); (5) Known allergy to shellfish; (6)History of, or positive test result at Screening for hepatitis C virus(HCV) antibody or hepatitis B virus (defined as positive for hepatitis Bsurface antigen [HBsAg] or hepatitis B core antibody [HBcAb]); (7)History of human immunodeficiency virus (HIV); (8) History of drug oralcohol abuse (as defined by the Investigator) within 2 years prior toScreening; (9) Current smoking or smoking within 6 months prior toScreening; (10) Any clinically significant (in the judgment of theInvestigator) infectious illness (e.g., cellulitis, abscess, pneumonia,septicemia) within 30 days prior to Screening; (11) Any active bacterialor viral infection (as assessed by the Investigator) at randomization;(12) History of clinically significant (in the judgment of theInvestigator) cardiovascular, dermatologic, endocrinologic,gastrointestinal, hematologic, hepatic, immunologic, metabolic,neurologic (other than MS), psychiatric, pulmonary, renal, urologic,and/or other major disease that would preclude participation in aclinical trial; (13) History of malignancy (subjects with basal cellcarcinoma that has been completely excised prior to study entry remaineligible); (14) History of severe allergic or anaphylactic reactions orknown drug hypersensitivity; (15) Any of the following abnormal bloodtests at Screening that are confirmed on repeat testing 2 weeks later:(a) alanine transaminase/serum glutamate-pyruvate transaminase(ALT/SGPT), or aspartate transaminase/scrum glutamic-oxaloacctictransaminase (AST/SGOT), or gamma-glutamyl-transferase (GGT) ≥2 timesthe upper limit of normal (ULN); (b) leukocytes <3500/mm³; and (c)eosinophils >0.7×10³/μL or >0.7 GI/L; (16) Any of the following abnormalurine tests at Screening confirmed by a second urinalysis 2 weeks later:(a) proteinuria (1+ or greater); (b) hematuria, without known etiology;(c) glycosuria, without known etiology; (17) Any previous treatment withFumaderm® or DMF (FAG-201); (18) Any type of live vaccine within 4 weeksprior to randomization, including but not limited tomeasles/mumps/rubella vaccine, varicella zoster virus vaccine, oralpolio vaccine, and nasal influenza vaccine; (19) Prior treatment withany of the following: cladribine, mitoxantrone, fingolimod, alemtuzumab,total lymphoid irradiation, T-cell or T-cell receptor vaccination, anytherapeutic monoclonal antibody, with the exception of Tysabri®(natalizumab) (see exclusion #20); (20) Treatment with Tysabri(natalizumub) within 1 year prior to randomization; (21) Treatment withany of the following medications or procedures within the 6 months priorto randomization: cyclosporine, azathioprine, teriflunomide,methotrexate, mycophenolate mofetil, intravenous immunoglobulin,plasmapheresis or cytapheresis; (22) Treatment with any of the followingwithin 2 weeks prior to randomization: subcutaneous or oral glatirameracetate, interferon-α, interferon-β; (23) Treatment with any of thefollowing within 4 weeks prior to randomization: Steroids (intravenous[IV] or oral corticosteroid treatment, including agents that may actthrough the corticosteroid pathway [e.g., low dose naltrexone]),4-aminopyridine or related products; and (24) Treatment with anotherinvestigational drug or approved therapy for investigational use withinthe 6 months prior to randomization.

5.1.5 Endpoints

The primary end points of this study are (1) the proportion of subjectswith a ≥2-fold rise in anti-tetanus serum immunoglobulin G (IgG) levelsfrom pre-vaccination to 4 weeks after Td vaccination; and (2) Theproportion of subjects with a ≥2-fold rise in anti-KLH serum IgG levelsfrom pre-vaccination to 4 weeks after the final KLH vaccination.

Secondary end points for this study are (1) the proportion of subjectswith a ≥4-fold rise in anti-tetanus serum IgG levels frompre-vaccination to 4 weeks after Td vaccination; (2) the proportion ofsubjects with a ≥4-fold rise in anti-KLH serum IgG levels frompre-vaccination to 4 weeks after the final KLH vaccination; (3) theproportion of subjects with a ≥2- and a ≥4-fold rise inanti-pneumococcal IgG levels from pre-vaccination baseline to 4 weeksafter PPSV23 vaccination; (4) Anti-tetanus, anti-KLH, andanti-pneumococcal immunoglobulin levels over time; (5) Change over timein lymphocyte subsets, including: T cells, B cells, NK cells (e.g.,Total T cells: CD4+/CD8+; Total B cells; Total NK); (6) Additionalanalysis of lymphocyte subsets which can include: Treg Panel (totalTreg, Resting/naïve Treg; and/or active Treg); T-cell panel (Naïve;Effector; Central/Effector Memory; and/or Activated (expressingHLA-DR/CD38)); (7) Myeloid NK panel (Monocytes:CD16+(non-classical)/CD16- (classical); Dendritic cells:myeloid/plasmacytoid; and/or NKs: CD56^(d1m)/CD56^(bright)); B cellpanel (Translational; Naïve; Memory: IgD+/IgD−; and/or Plasmablast); and(8) Safety parameters, including incidence of all AEs, including thoseleading to treatment discontinuation and study withdrawal, and allserious adverse events (SAEs); clinical laboratory shifts in reportedvalues; and clinically significant changes in vital sign measurements.

In addition, Ribonucleic acid (RNA) and peripheral blood mononuclearcells (PBMCs) are collected in certain subjects evaluate lymphocytesubsets. PBMCs are separated and frozen for testing at a later time atthe Sponsor's discretion.

5.1.6 Treatment Schedule

Approximately 68 subjects are enrolled in the study. Subjects arerandomized in a 1:1 ratio to Group 1 (DMF treatment plus immunizations)or Group 2 (immunizations alone).

Group 1 subjects are treated with DMF 120 mg BID for first 7 days and240 mg BID thereafter up to 48 weeks. Table 1 shows a detailed scheduleof events for Group 1 subjects.

At Week 24, subjects in Group 1 receive Td, PPSV23, and KLHvaccinations. At 2 and 4 weeks after the Week 24 vaccination, subjectsreceive an additional KLH vaccination (Weeks 26 and 28). Anti-tetanusand anti-pneumococcal IgG titers are measured just prior to and at 4 and8 weeks after the Week 24 vaccinations (i.e., Weeks 24, 28, and 32).Anti-KLH IgG titers are measured just prior to and at 4, 8, and 12 weeksafter the Week 24 vaccination (i.e., Weeks 24, 28, 32, and 36).(Anti-tetanus titers are also measured at Screening, as part of theeligibility criteria). Blood samples for lymphocyte subset analysis, aswell as blood samples for determination of each subject's complete bloodcount (CBC) with differential, are collected at Screening, Baseline (Day1), and Weeks 12, 24, 36, and 48. Clinical samples for analysis of bloodchemistries and urinalysis are collected at Screening and at Weeks 24and 48. A serum pregnancy test is performed at Screening, as part of theeligibility criteria. Urine pregnancy tests are performed at Baseline(Day 1), and Weeks 12, 24, 26, 28, 32, 36, and 48. Vital signs, AEs, andconcomitant therapies are assessed at every clinic visit. A finalfollow-up clinic visit at which safety assessments are performed occurs4 weeks after the final dose of DMF in subjects who do not continuetreatment with commercial DMF. Subjects who plan to continue treatmentwith commercial DMF after Week 48 are contacted by telephone 2-4 weeksafter their last study dose to ensure transition has taken place. If forany reason they have not started commercial DMF, they are required tohave a final follow-up clinic visit 4 weeks after their last study dose.

Group 2 subjects receive the same vaccinations and assessments over a12-week period according to the schedule in Group 1, but withvaccinations starting on Day 1. That is, subjects receive Td, PPSV23,and KLH vaccinations at Baseline (Day 1) and an additional KLHvaccination at Weeks 2 and 4. Anti-tetanus and anti-pneumococcal IgGtiters are measured just prior to and at 4 and 8 weeks after Baseline(Day 1). Anti-KLH IgG titers are measured just prior to and at 4, 8, and12 weeks after the Day 1 vaccination. (Anti-tetanus titers are alsomeasured at Screening, as part of the eligibility criteria). Bloodsamples for lymphocyte subset analysis (as well as CBC with differentialfor laboratory safety analysis) are collected at Screening, Baseline(Day 1), and Week 12. Clinical samples for analysis of blood chemistriesand urinalysis are collected at Screening and Week 12 and at Screening,Baseline (Day 1), and Week 12, respectively. A serum pregnancy test isperformed at Screening, as part of the eligibility criteria. Urinepregnancy tests are performed at Baseline (Day 1), and Weeks 2, 4, and12. Vital sign measurements, AEs, and concomitant therapies areperformed at every clinic visit. After completing the study, Group 2subjects may be eligible to begin treatment with commercial DMF ifdeemed appropriate. Table 2 shows a detailed schedule of events forGroup 2 subjects.

Subjects randomized to Group 1 (DMF treatment plus immunizations) have 9clinic visits: Screening, Baseline (Day 1), and Weeks 12, 24, 26, 28,32, 36, and 48. Subjects who do not continue treatment with commercialDMF after Week 48 have a final follow-up clinic visit 4 weeks after thefinal dose. Subjects who plan to continue treatment with commercial DMFafter Week 48 are contacted by telephone 2-4 weeks after their laststudy dose to ensure transition has taken place. If for any reason theyhave not started commercial DMF they are required to have a finalfollow-up clinic visit 4 weeks after their last study dose.

Subjects randomized to Group 2 (immunizations alone) have 6 clinicvisits: Screening, baseline (Day 1), and Weeks 2, 4, 8, and 12.

5.1.7 Efficacy Analysis

Analysis of the primary endpoint for the Td and KLH vaccinations isbased on evaluable subjects (i.e., subjects who are appropriatelyvaccinated per protocol; are ≥70% compliant with DMF [Group 1 only], andhave non-missing IgG levels at pre-vaccination and 4 weeks after finalvaccination).

TABLE 1 Group 1 Schedule of Events Screening Week 48 (w/in 28 Week WeekWeek Week Week Week (Day Follow-Up days 12 (Day 24 (Day 26 (Day 28 (Day32 (Day 36 (Day 336 ± 3 (4 weeks ± 5 Tests and before Baseline 84 ± 3168 ± 3 182 ± 3 196 ± 3 224 ± 3 252 ± 3 days)/ days after Assessments¹Baseline) (Day 1) days) days) days) days) days) days) W/D² final dose)²Informed consent³ X Medical history X Physical X X examination Vitalsigns⁴ X X X X X X X X X X Hepatitis B and C X screen Hematology (CBCwith differential) X X X  X⁵ X X X Blood chemistry X  X⁵ X X UrinalysisX  X⁵ X X Scrum pregnancy X test⁶ Urine pregnancy X X X X X X X X test⁶Dispense DMF X X X X X X DMF DMF is to be taken as 120 mg BID for thefirst 7 days and thereafter as 240 mg BID. administration Subjects areto be instructed to take DMF orally, by swallowing the capsules wholewithout chewing, and with or without food. Tetanus toxoid X vaccine⁷PPSV23 vaccine⁷ X Anti-tetanus and Anti-  X⁵  X⁵ X anti-pneumococcaltetanus antibody assays only KLH vaccine⁷ X X X KLH antibody  X⁵  X⁵ X Xassay Lymphocyte X X X  X⁵ X X X subset analysis Concomitant X X X X X XX X X X therapy and procedures SAE recording X X X X X X X X X X AErecording X X X X X X X X X RNA collection⁸ X X  X⁵ X X X PBMCcollection⁸ X  X⁵ X X ¹All tests and assessments will be performedbefore dispensing study treatment. ²Subjects who discontinue treatmentprematurely are withdrawn from the study and have a Withdrawal visitwithin 4 weeks after taking their final study dose. Subjects who do notcontinue treatment with commercial DMF after Week 48/early withdrawalhave a final follow-up clinic visit 4 weeks after their final studydose. Subjects who plan to continue treatment with commercial DMF afterWeek 48 are contacted by telephone 2-4 weeks after their last study doseto ensure transition has taken place. If for any reason they have notstarted commercial DMF they are required to have a final follow-upclinic visit 4 weeks after their last study dose. ³Written informedconsent will be obtained prior to performing any study-relatedprocedures, and may be obtained prior to Screening if a washout periodis required for prior therapy. ⁴Vital signs include height (measured atScreening only), weight, diastolic and systolic blood pressure, heartrate, and temperature. Subjects will be seated for 5 minutes prior tohaving their pulse and blood pressure measured. ⁵Blood as well as urinesamples will be collected prior to immunization. ⁶Females ofchildbearing potential only. Results will be known to be negative priorto dispensing DMF and immunization. ⁷Subjects are observed for anysevere local or systemic reactions for 45 minutes followingimmunization. ⁸RNA and PBMC are collected in subjects who have signed aseparate Future Scientific Research informed consent form.

TABLE 2 Group 2 Schedule of Events Screening Week 2 Week 4 Week 8 Week12 Tests and (within 28 days Baseline (Day 14 ± 3 (Day 28 ± 3 (Day 56 ±3 (Day 84 ± 3 Assessments¹ before Baseline) (Day 1) days) days) days)days)/W/D² Informed X consent³ Medical history X Physical X examinationVital signs⁴ X X X X X X Hepatitis B and X C screen Hematology X  X⁵ X(CBC with differential) Blood chemistry X X Urinalysis X  X⁵ X Serum Xpregnancy test⁶ Urine pregnancy X X X X test⁶ Tetanus toxoid X vaccine⁷PPV23 vaccine⁷ X Anti-tetanus and Anti-  X⁵  X⁵ X anti- tetanuspneumococcal only antibody assays KLH vaccine⁷ X X X KLH antibody  X⁵ X⁵ X X assay Lymphocyte X  X⁵ X subset analysis Concomitant X X X X X Xtherapy and procedures SAE recording X X X X X X AE recording X X X X XRNA collection⁸  X⁵ PBMC  X⁵ X collection⁸ ¹All tests and assessmentswill be performed prior to immunization. ²In subjects who are withdrawnfrom the study, a Withdrawal Visit is performed within 4 weeks aftertheir last immunization. ³Written informed consent will be obtainedprior to performing any study-related procedures, and may be obtainedprior to Screening if a washout period is required for prior therapy.⁴Vital signs include height (measured at Screening only), weight,diastolic and systolic blood pressure, heart rate, and temperature.Subjects will be seated for 5 minutes prior to having their pulse andblood pressure measured. ⁵Blood as well as urine samples will becollected prior to immunization. ⁶Females of childbearing potentialonly. Results will be known to be negative prior to immunization.⁷Subjects are observed for any severe local or systemic reactions for 45minutes following immunization. ⁸RNA and PBMC are collected in subjectswho have signed a separate Future Scientific Research informed consentform.

5.2 Example 2: An Open-Label Study to Assess the Immune Response toVaccination in Tecfidere® (BG00012)-treated Versus Interferon-treatedSubjects with Relapsing Forms of Multiple Sclerosis

5.2.1 List of Abbreviations

The following abbreviations and definitions are used in this studyprotocol:

AE adverse event BID twice daily CI confidence interval CRF case reportform EDC electronic data capture GCP Good Clinical Practice ICF informedconsent form ICH International Conference on Harmonisation IFNinterferon IgG immunoglobulin G MCV4 meningococcal polysaccharidediphtheria conjugate vaccine (quadrivalent) MS multiple sclerosis PHIprotected health information PPSV23 23-valent pneumococcalpolysaccharide vaccine RRMS relapsing-remitting multiple sclerosis SAEserious adverse event SUSAR suspected unexpected serious adversereaction Td tetanus diphtheria toxoids vaccine US United States

5.2.2 Synopsis

This is a brief summary of the study protocol.

Existing Multiple Sclerosis Treatment (Not Supplied by the Sponsor)include Tecfidera® (dimethyl fumarate) and non-pegylated interferon(IFN; e.g., Avonex®, Betascron®, Rebif®), Extavia®).

5.2.2.1. Study Objectives

Primary

The primary objective of the study is to evaluate the immune response tovaccination with Td in subjects with relapsing forms of MS who have beentreated with Tecfidera versus those treated with non-pegylated IFN.

Secondary

The secondary objective of the study is to evaluate the immune responseto vaccination with PPSV23 and MCV4.

5.2.2.2. Study Endpoints

Primary

The primary endpoint of the study is:

-   -   The proportion of subjects with a ≥2-fold rise in anti-tetanus        serum immunoglobulin G (IgG) levels from pre-vaccination to 4        weeks after Td vaccination.

Secondary

The secondary endpoints of the study are:

-   -   The proportion of subjects with a ≥4-fold rise in anti-tetanus        serum IgG levels from pre-vaccination to 4 weeks after Td        vaccination.    -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti-pneumococcal serum IgG levels against serotypes 3 and 8        from pre-vaccination to 4 weeks after PPSV23 vaccination.    -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti-meningococcal serum IgG levels against serotype C from        pre-vaccination to 4 weeks after MCV4 vaccination.    -   The geometric mean titer ratios from pre-vaccination to 4 weeks        after Td, PPSV23, and MCV4 vaccinations.    -   Incidence of adverse events (AEs) and serious adverse events        (SAEs).    -   Clinical laboratory shifts in reported values.    -   Clinically significant changes in vital sign measurements.

Exploratory

The exploratory endpoints of the study are:

-   -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti-diphtheria toxoid serum IgG levels from pre-vaccination to        4 weeks after MCV4 vaccination.    -   The anti-diphtheria geometric mean titer ratio from        pre-vaccination to 4 weeks after MCV4 vaccination.    -   The proportion of subjects with anti-tetanus and        anti-meningococcal seroprotective levels at 4 weeks after Td and        MCV4 vaccinations.

5.2.2.3. Study Design

This is an open-label, multicenter study to evaluate the immune responseto vaccination in subjects with relapsing forms of MS who have beentreated for at least 6 months with the approved dose of Tecfidera (240mg twice daily [BID]) or who have been treated for at least 3 monthswith the approved dose of a non pegylated IFN (e.g., Avonex, Betaseron,Rebif, Extavia).

After a 28-day Screening Period, eligible subjects will be enrolled andassigned as appropriate into either Group 1 (currently treated withTecfidera) or Group 2 (currently treated with non-pegylated IFN).Throughout the study, subjects will remain on their existing, stabledosing regimen of Tecfidera or non pegylated IFN.

Subjects will come to the clinic on Day 1 and have blood samples drawnfor pre vaccination anti-tetanus, anti pneumococcal, anti meningococcal,and anti-diphtheria TgG titers. All subjects will receive 3vaccinations: Td, PPSV23, and MCV4. They will return to the clinic atWeek 4 for their final study visit, at which time blood samples will bedrawn for post-vaccination IgG titers.

Subjects who receive at least 1 dose of a vaccine should remain in thestudy and attend the Week 4 Visit. Subjects who receive at least 1 doseof a vaccine but would like to withdraw from the study prematurely willbe asked to return to the clinic for an Early Withdrawal Visit, at whichtime blood samples will be drawn for IgG titers.

Safety evaluations in this study will include blood samples for completeblood count with differential and blood chemistry, urine pregnancytests, and vital signs at Day 1 and Week 4, as well as ongoingcollection of AEs, SAES, and concomitant medications.

The subjects' neurologist or primary healthcare provider will managetheir MS care before, during, and after study participation.

This study will be conducted at approximately 10 to 15 sites in theUnited States, and the number of planned subjects will be 70(approximately 35 in each group)

5.2.2.4. Study Population

Subjects with relapsing forms of MS between the ages of 18 and 55 years,inclusive, with a known history of tetanus immunization and on a stableapproved dose of either Tecfidera (240 mg BID) for ≥6 months or a nonpegylated IFN for ≥3 months.

5.2.2.5. Treatment Groups

Subjects treated with Tecfidera will be assigned to Group 1. Subjectstreated with non pegylated IFN will be assigned to Group 2.

All subjects will receive the same 3 vaccinations on Day 1intramuscularly in the specified order:

-   -   1. Td 0.5 mL    -   2. PPSV23 0.5 mL    -   3. MCV4 0.5 mL

5.2.2.6. Study Duration

Subjects will have 3 clinic visits: Screening, Day 1, and Week 4. Theduration of study participation will be approximately 8 weeks.

5.2.2.7. Criteria for Evaluation

Efficacy

Anti-tetanus, anti pneumococcal, anti meningococcal, and anti-diphtheriaIgG levels at pre vaccination (Day 1) and at Week 4

Safety

The following safety assessments will be performed:

-   -   Vital sign measurements    -   Physical examination    -   Hematology and blood chemistry    -   Serum and urine pregnancy testing    -   Monitoring and recording of AEs    -   Monitoring and recording of concomitant therapy and procedures

5.2.2.8. Statistical Methods

No formal statistical testing is planned. The proportion of respondersto each vaccine antigen will be estimated with 95% confidence intervals(CIs) using the exact method. Differences in the proportion of subjectswith an antibody response between Group 1 and Group 2 will also beestimated with 95% CIs using the exact method. The IgG level to eachantigen will also be summarized by geometric mean concentration for eachgroup with 95% CI as well as the ratio between the 2 groups.

All safety data will be summarized using descriptive statistics.Incidence of AEs will be summarized using frequency distribution tablesby group, overall, by severity, and by relationship to vaccines. Changefrom baseline in laboratory values and vital signs will also bedescriptively summarized by group.

No interim analysis will be performed.

5.2.2.9. Sample Size Determination

The sample size for this study is not based on formal hypothesistesting, but on the precision of estimated response rates. The 95% CIsfor the difference between Groups 1 and 2 in the proportion ofvaccination responders will be provided to quantify the variability inthe differences of response rates.

Assuming a response rate of 95% to Td in Group 2 (the reference group)and a range of hypothetical response rates in Group 1 (the test group),an evaluable size of 32 subjects per group would provide the following95% CIs for the difference between groups (Group 1-Group 2) in theproportion of vaccination responders:

Group 1 Difference Response (Group 1 - 95% CI for the Rate Group 2)Difference 95%  0 [−13.8%, 13.8%] 75% −20% [−39.9%, 0.1%] 70% −25%[−45.7%, −4.3%] 65% −30% [−51.3%, −8.7%] 55% −40% [−61.9%, −18.1%]

The analysis population for the primary endpoint of ≥2-fold rise inanti-tetanus serum IgG levels comprises subjects who are appropriatelyvaccinated per protocol, have not taken any concomitant medication thatcould impact immune responses, and who have nonmissing pre-vaccinationand post vaccination IgG levels with a pre-vaccination level less thanor equal to one half the upper limit of detection for the assay. It isanticipated that a total sample size of approximately 70 subjects (35subjects per group) will need to be enrolled in order to obtain a totalof 64 evaluable subjects (32 subjects per group). The sample sizedetermination takes into account an approximate 10% loss of evaluablesubjects.

5.2.3 Schedule of Events

TABLE 3 Schedule of Events Screening Week 4 (Day 28 ± 3 (Within 28 daysdays) or Early Tests and Assessments Before Day 1) Day 1 WithdrawalInformed Consent¹ X Inclusion/Exclusion Criteria X X Medical History XVital Signs² X X X Physical Examination X Hematology (CBC With X X³ XDifferential) Blood Chemistry X X³ X Pregnancy Tests⁴ Serum Urine UrineBlood Collection for Anti-Tetanus X³ X Anti-Tetanus, OnlyAnti-Pneumococcal Anti-Meningococcal, and Anti-Diphtheria IgG TitersVaccines Td⁵ X PPSV23⁵ X MCV4⁵ X SAE and Concomitant Therapy andProcedures Recording X ------------------------------------------ X AEsRecording X ---------------------- X AEs = adverse events; CBC =complete blood count; IgG = immunoglobulin G; MCV4 = meningococcalpolysaccharide diphtheria conjugate vaccine (quadrivalent); PPSV23 =23-valent pneumococcal polysaccharide vaccine; SAEs = serious adverseevents; Td = tetanus diphtheria toxoids vaccine. ¹Written informedconsent will be obtained prior to performing any study-relatedprocedures. ²Vital signs will include height (measured at Screeningonly), weight, diastolic and systolic blood pressure, heart rate, andtemperature. Subjects will be seated for 5 minutes prior to having theirpulse and blood pressure measured. ³Blood samples will be collectedprior to vaccine administration. ⁴Females of childbearing potentialonly. Results will be known to be negative prior to vaccineadministration. ⁵Subjects will be observed in the clinic for at least 30minutes following their final vaccine administration.

5.2.4 Study Objectives and Endpoints

5.2.4.1. Objectives

Primary Objective

The primary objective of the study is to evaluate the immune response tovaccination with Td in subjects with relapsing forms of MS who have beentreated with Tecfidera versus those treated with non pegylated IFN.

Secondary Objective

The secondary objective of the study is to evaluate the immune responseto vaccination with PPSV23 and MCV4.

5.2.4.2. Endpoints

Primary Endpoint

The proportion of subjects with a ≥2-fold rise in anti tetanus serumimmunoglobulin G (IgG) levels from pre-vaccination to 4 weeks after Tdvaccination.

Secondary Endpoints

-   -   The proportion of subjects with a ≥4 fold rise in anti tetanus        serum IgG levels from pre vaccination to 4 weeks after Td        vaccination.    -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti pneumococcal serum IgG levels against serotypes 3 and 8        from pre vaccination to 4 weeks after PPSV23 vaccination.    -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti meningococcal serum IgG levels against serotype C from        pre-vaccination to 4 weeks after MCV4 vaccination.    -   The geometric mean titer ratios from pre-vaccination to 4 weeks        after Td, PPSV23, and MCV4 vaccinations.    -   Incidence of adverse events (AEs) and serious adverse events        (SAEs).    -   Clinical laboratory shifts in reported values.    -   Clinically significant changes in vital sign measurements.

Exploratory Endpoints

-   -   The proportion of subjects with a ≥2-fold and a ≥4-fold rise in        anti-diphtheria toxoid serum IgG levels from pre-vaccination to        4 weeks after MCV4 vaccination.    -   The anti-diphtheria geometric mean titer ratio from        pre-vaccination to 4 weeks after MCV4 vaccination.    -   The proportion of subjects with anti-tetanus and        anti-meningococcal seroprotective levels at 4 weeks after Td and        MCV4 vaccinations.

5.2.5 Study Design

5.2.5.1. Study Overview

This is an open-label, multicenter study to evaluate the immune responseto vaccination in subjects with relapsing forms of MS who have beentreated for at least 6 months with the approved dose of Tecfidera (240mg BID) or who have been treated for at least 3 months with an approveddose of a non pegylated IFN (e.g., Avonex, Betaseron, Rebif, Extavia).This study will be conducted at approximately 10 to 15 sites in the US.

After a 28-day Screening Period, approximately 70 eligible subjects willbe enrolled and assigned as appropriate into either Group 1 (currentlytreated with Tecfidera) or Group 2 (currently treated with non-pegylatedIFN), with approximately 35 subjects in each group.

Throughout the study, subjects will remain on their existing, stabledosing regimen of Tecfidera or non pegylated IFN.

Subjects will come to the clinic on Day 1 and have blood samples drawnfor pre-vaccination anti-tetanus, anti pneumococcal, anti meningococcal,and anti diphtheria IgG titers. All subjects will receive 3vaccinations: Td, PPSV23, and MCV4. They will return to the clinic atWeek 4 for their final study visit, at which time blood samples will bedrawn for post-vaccination IgG titers.

Subjects who receive at least 1 dose of a vaccine should remain in thestudy and attend the Week 4 Visit. Subjects who receive at least 1 doseof a vaccine but would like to withdraw from the study prematurely willbe asked to return to the clinic for an Early Withdrawal Visit, at whichtime blood samples will be drawn for IgG titers.

Safety evaluations in this study will include blood samples for completeblood count with differential and blood chemistry, urine pregnancytests, and vital signs at Day 1 and Week 4, as well as ongoingcollection of AEs, SAEs, and concomitant medications as detailed inTable 3: Schedule of Events.

The subjects' neurologist or primary healthcare provider will managetheir MS care before, during, and after study participation.

5.2.5.2. Overall Study Duration and Order of Study Procedures

In both groups, subjects will have 3 clinic visits: Screening, Day 1,and Week 4. The duration of study participation will be approximately 8weeks. The following sections outline the timing and order of proceduresconducted at each study visit. The procedures are listed in the order ofpreferred collection by the Sponsor to enhance data clarity. Alteringthe order is not considered a protocol deviation with the exception ofthe timing of blood collection in relation to vaccination (i.e., bloodsamples for pre-vaccination titers will be collected before vaccinationsare given) and the order of vaccine administration.

5.2.5.3. Screening Visit

Subjects will be screened and meet eligibility criteria for the studywithin 28 days prior to study entry.

At the Screening Visit, informed consent will be given before anyscreening activities are conducted. Other procedures to be conductedduring the Screening Visit, in preferred order, are listed below:

-   -   Concomitant therapy and procedure recording    -   Medical history    -   Vital signs    -   Physical examination    -   Review of inclusion/exclusion criteria (except laboratory        results)    -   Collection of blood samples for anti-tetanus IgG titer,        hematology, blood chemistry, and serum pregnancy test    -   AE assessment and reporting

5.2.5.4. Day 1 Visit

Subjects who pass screening will return to the clinic for the Day 1Visit.

At the Day 1 Visit, the following procedures will be completed beforestudy vaccines are administered and are listed in preferred order:

-   -   AE and SAE assessment and recording    -   Concomitant therapy and procedure recording    -   Review of inclusion/exclusion criteria    -   Urine pregnancy test (females only)—do not vaccinate subject        unless pregnancy has been excluded with a negative pregnancy        test    -   Vital signs    -   Collection of blood samples for anti-tetanus, anti-pneumococcal,        anti meningococcal, and anti-diphtheria IgG titers; hematology;        and blood chemistry

After completing these assessments, study vaccines will be administeredin the following order:

-   -   1. Td    -   2. PPSV23    -   3. MCV4

Subjects will remain at the clinic for at least 30 minutes after theirfinal vaccination for observation.

5.2.5.5. Week 4/Early Withdrawal Visit

Subjects in both groups will have a clinic visit 4 weeks aftervaccination. Subjects who have received at least 1 vaccination butwithdraw prematurely from the study will be asked to return to theclinic for an Early Withdrawal Visit.

Procedures to be conducted during the Week 4/Early Withdrawal Visit, inpreferred order, are listed below:

-   -   AE and SAE assessment and recording    -   Concomitant therapy and procedure recording    -   Urine pregnancy test (females only)    -   Vital signs    -   Collection of blood samples for anti-tetanus, anti-pneumococcal,        anti meningococcal, and anti-diphtheria IgG titers; hematology;        and blood chemistry

5.2.5.6. End of Study

The end of study is last subject, last visit for final collection ofdata.

5.2.6 Selection of Subjects

5.2.6.1. Inclusion Criteria

Unless otherwise specified, to be eligible to participate in this study,candidates will meet the following eligibility criteria at Screening andon Day 1 or at the timepoint specified in the individual eligibilitycriterion:

-   -   1. Ability to understand the purpose and risks of the study and        provide signed and dated informed consent and authorization to        use protected health information (PHI) in accordance with        national and local subject privacy regulations.    -   2. Aged 18 to 55 years old, inclusive, at the time of informed        consent.    -   3. Women of childbearing potential will practice appropriate        contraception (per the local Tecfidera or non-pegylated IFN        prescribing information) as determined by the Investigator.    -   4. Will have a confirmed diagnosis of RRMS per the 2010 McDonald        criteria [Polman 2011].    -   5. Will have a known tetanus immunization history with most        recent tetanus vaccination given 2 to 15 years prior to        Screening and an anti-tetanus IgG titer at Screening that is        less than or equal to one-half the upper limit of detection for        the assay.    -   6. Will have been on a stable approved dose of Tecfidera (240 mg        BID) [Group 1] for ≥6 months or on a stable approved dose of a        non-pegylated IFN (e.g., Avonex, Betaseron, Rebif, Extavia)        [Group 2] for ≥3 months prior to Day 1.

Note: Subjects will have received their MS treatment as monotherapy forthe required duration, except during treatment of relapses.

5.2.6.2. Exclusion Criteria

Unless otherwise specified, candidates will be excluded from study entryif any of the following exclusion criteria exist at Screening and on Day1 or at the timepoint specified in the individual eligibility criterion:

Medical History

-   -   1. Clinical relapse requiring treatment within 30 days prior to        Day 1.    -   2. Pneumococcal vaccination within 5 years prior to Screening.    -   3. Previous exposure to meningococcal vaccines.    -   4. Known hypersensitivity to Td, PPSV23, or MCV4 or their        components.    -   5. History of hepatitis C or hepatitis B virus.    -   6. History of human immunodeficiency virus.    -   7. History of drug or alcohol abuse (as defined by the        Investigator) within 2 years prior to Screening.    -   8. Current smoker or smoking within 6 months prior to Screening.    -   9. Any clinically significant infectious illness (e.g.,        cellulitis, abscess, pneumonia, septicemia) within 30 days prior        to Screening.    -   10. Any active bacterial or viral infection or an oral        temperature ≥38.0° C./100.4° F. on Day 1 or within 3 days prior        to Day 1. Subjects with a clinically significant active        infection or measured oral (sublingual) temperature ≥38.0°        C./100.4° F. should have vaccinations postponed until the        subject's temperature remains below 38.0° C./100.4° F. for at        least 3 days and the subject's acute illness has resolved.    -   11. History of clinically significant cardiovascular,        dermatologic, endocrinologic, gastrointestinal, hematologic,        hepatic, immunologic, metabolic, neurologic (other than MS),        psychiatric, pulmonary, renal, urologic, and/or other major        disease that may confound safety or efficacy assessments.    -   12. History of malignancy (subjects with basal cell carcinoma        that has been completely excised prior to study entry remain        eligible).    -   13. History of severe allergic reactions, anaphylactic        reactions, or known drug hypersensitivity to Tecfidera or        fumaric acid esters.    -   14. Any abnormal laboratory assessment judged to be clinically        significant by the Investigator at Screening.        -   Note: The following analytes are strictly exclusionary:            -   leukocytes <2500/mm³            -   lymphocytes <500/mm³            -   alanine transaminase or aspartate transaminase >2 times                the upper limit of normal

Treatment History

-   -   15. Any type of vaccine, with the exception of inactivated        influenza vaccination (the flu shot), within 4 weeks prior to        Day 1 (the inactivated flu shot is allowed; the intranasal live        vaccine is not allowed).    -   16. Prior treatment with any of the following:        -   cladribine        -   mitoxantrone        -   fingolimod        -   total lymphoid irradiation        -   T-cell or T-cell-receptor vaccination        -   any therapeutic monoclonal antibody, with the exception of            Tysabri® (natalizumab) (see exclusion #17).    -   17. Prior treatment with Tysabri (natalizumab) within 1 year        prior to Screening.    -   18. Prior treatment with any of the following medications or        procedures within 6 months prior to Screening:        -   cyclosporine        -   azathioprine        -   methotrexate        -   mycophenolate mofetil        -   intravenous immunoglobulin        -   plasmapheresis or cytapheresis        -   subcutaneous or oral glatiramer acetate    -   19. Treatment with any immunosuppressive drug or regimen within        3 months prior to Day 1, including but not limited to chronic        steroid use (defined as continuous [>14 days] use of intravenous        or oral corticosteroid treatment, with a dosage equivalence        of >20 mg/day of oral prednisone) or agents that may act through        the corticosteroid pathway (e.g., low dose naltrexone).    -   20. Treatment with any investigational drug or approved therapy        for investigational use within the 6 months prior to Day 1 or        during the study.

Miscellaneous

-   -   21. Female subjects who are currently pregnant or breast-feeding        or planning to become pregnant while in the study.    -   22. Current enrollment in any other investigational study within        6 months prior to Day 1.        -   Note: Current enrollment in an observational study that does            not involve drugs, vaccines, or medical devices is allowed.    -   23. Unwillingness or inability to comply with the requirements        of the protocol including the presence of any condition        (physical, mental, or social) that is likely to affect the        subject's ability to comply with the protocol.    -   24. Any other reasons that, in the opinion of the Investigator        and/or the Sponsor, the subject is determined to be unsuitable        for enrollment in this study.

5.2.7 Treatment of Subjects

5.2.7.1. Vaccinations

On Day 1, following all other assessments, subjects in both groups willreceive the following vaccinations intramuscularly in the specifiedorder:

-   -   1. Td (Tenivac®, 0.5 mL)    -   2. PPSV23 (Pneumovax® 23, 0.5 mL)    -   3. MCV4 (Menveo®, 0.5 mL)

5.2.7.2. Concomitant Therapy

A concomitant therapy is any drug or substance administered from thetime the subject is enrolled in the study until the subject's finalstudy visit.

5.2.7.3. Disallowed Concomitant Therapy

Concomitant therapy with any of the following is not allowed, unlessapproved by the Medical Monitor, or as otherwise described in thisprotocol:

-   -   Any treatment for MS, such as chronic immunosuppressant therapy        or other immunomodulatory treatments (including, but not limited        to: glatiramer acetate, natalizumab, cyclophosphamide,        methotrexate, azathioprine, fingolimod, alemtuzumab,        teriflunomide, or related products, etc.), with the exception of        treatments required as a condition for study eligibility and        treatments for acute management of relapses.    -   Any investigational product, including investigational        symptomatic therapies for MS and investigational therapies or        vaccines for non-MS indications.    -   Any systemic steroid therapy including, but not limited to, oral        corticosteroids (e.g., prednisone) or periodic (e.g., monthly)        treatment with intravenous methylprednisolone, except for        treatment of a relapse. Steroids that are administered by        nonsystemic routes (e.g., topical, inhaled) are allowed.    -   Total lymphoid irradiation, cladribine, T-cell or        T-cell-receptor vaccination, any therapeutic monoclonal        antibody, mitoxantrone, cyclosporine, intravenous        immunoglobulin, plasmapheresis, or cytapheresis.    -   Live or live-attenuated vaccines.

Subjects should be instructed not to start taking any new medications,including nonprescribed drugs, unless they have received permission fromthe Investigator.

5.2.7.4. Concomitant Procedures

A concomitant procedure is any therapeutic intervention (e.g.,surgery/biopsy, physical therapy) or diagnostic assessment (e.g., bloodgas measurement, bacterial cultures) performed between the time thesubject is enrolled in the study until the subject's final study visit.

The use of concomitant therapies or procedures defined above will berecorded on the subject's case report form (CRF), according toinstructions for CRF completion. AEs related to administration of thesetherapies or procedures will be documented on the appropriate CRF.

5.2.8 Efficacy Assessments

Blood samples will be collected for anti-tetanus, anti pneumococcal,anti meningococcal, and anti-diphtheria IgG titers before vaccination onDay 1 and after vaccination at Week 4 or the Early Withdrawal Visit.

Refer to Table 3: Schedule of Events, for the timing of assessments.

5.2.9 Safety Assessments

5.2.9.1. Clinical Safety Assessments

The following clinical assessments will be performed during the study:

-   -   Vital sign measurements    -   Physical examination    -   Monitoring/recording of AEs    -   Monitoring/recording of concomitant therapy and procedures

Refer to Table 3: Schedule of Events, for the timing of assessments.

5.2.9.2. Laboratory Safety Assessments

The following laboratory tests will be performed during the study:

-   -   Hematology: hemoglobin, hematocrit, red blood cell count, white        blood cell count (with differential), and platelet count    -   Blood chemistry: sodium, potassium, chloride, total bilirubin,        alanine transaminase, aspartate transaminase, gamma glutamyl        transferase, blood urea nitrogen, and creatinine    -   Urine and serum pregnancy tests

Refer to Table 3: Schedule of Events, for the timing of assessments.

5.2.10 References for Example 2

-   Olberg H K, Cox R J, Nostbakken J K, et al. Immunotherapies    influence the influenza vaccination response in multiple sclerosis    patients: an explorative study. Mult Scler. 2014; 20(8):1074-1080.-   Polman C H, Reingold S C, Banwell B, et al. Diagnostic criteria for    multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann    Neurol. 2011; 69(2):292-302.-   Schwid S R, Thorpe J, Sharief M, et al. Enhanced benefit of    increasing interferon beta-1a dose and frequency in relapsing    multiple sclerosis: the EVIDENCE Study. Arch Neurol. 2005;    62(5):785-92.

6. INCORPORATION BY REFERENCE

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties.

What is claimed is:
 1. A method of treating or preventing multiplesclerosis in a subject in need thereof, comprising (a) administering tothe subject a first dose of a pharmaceutical composition for a firstdosing period, wherein the pharmaceutical composition comprises afumarate agent selected from the group consisting of monomethylfumarate, a compound that metabolizes into monomethyl fumarate in vivo,a deuterated analog thereof, a pharmaceutically acceptable salt thereof,and a combination thereof; (b) administering a vaccine to the subject;and (c) administering to the subject a second dose of the pharmaceuticalcomposition for a second dosing period, wherein the second dosing periodis after the first dosing period.
 2. The method of claim 1, wherein thefumarate agent is monomethyl fumarate, dimethyl fumarate, or acombination thereof.
 3. The method of claim 1 or 2, wherein the fumarateagent is dimethyl fumarate.
 4. The method of claim 3, wherein the firstdose is a daily amount of about 480 mg dimethyl fumarate.
 5. The methodof any of claims 1-4, wherein the second dose is lower than the firstdose.
 6. The method of any of claims 1-5, wherein the second dose is 0mg fumarate agent.
 7. The method of any of claims 1-6, furthercomprising administering a titration dose of the pharmaceuticalcomposition prior to the first dosing period.
 8. The method of claim 7,wherein the fumarate agent is dimethyl fumarate and the titration doseis a daily amount of about 240 mg dimethyl fumarate.
 9. The method ofany of claims 1-8, wherein the first and second doses of the fumarateagent are in a form of microtablets, micropellets, granules, capsules,or tablets.
 10. The method of any of claims 1-9, wherein the dimethylfumarate is in a form of microtablets, and wherein the microtablets areenterically coated.
 11. The method of any of claims 1-10, wherein thestep of administering the vaccine occurs before or during the firstdosing period.
 12. The method of any of claims 1-11, wherein the vaccineinduces a T cell-dependent immune response.
 13. The method of claim 12,wherein the vaccine induces a T cell-dependent anamnestic humoral immuneresponse.
 14. The method of claim 12, wherein the vaccine induces a Tcell-dependent neoantigen immune response.
 15. The method of any ofclaims 1-11, wherein the vaccine induces a T cell-independent immuneresponse.
 16. The method of any of claims 1-15, wherein serum antibodylevel induced by the vaccine in the subject is lower compared to averageserum antibody level observed in subjects administered with the vaccinebut not the fumarate agent, and the second dose is less than the firstdose.
 17. The method of any of claims 1-15, wherein serum antibody levelinduced by the vaccine in the subject increases less than 4-fold frompre-vaccination to 4 weeks after vaccination, and the second dose isless than the first dose.
 18. The method of any of claims 1-17, whereinthe vaccine is a live or inactive vaccine.
 19. The method of claim 18,wherein the vaccine is an inactive vaccine.
 20. The method of any ofclaims 1-17, wherein the vaccine is a vaccine selected from the groupconsisting of tetanus diphtheria toxoids vaccine, keyhole limpethemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof.21. The method of any of claims 1-17, wherein the vaccine is tetanusdiphtheria toxoids vaccine.
 22. The method of any of claims 1-17,wherein the vaccine is keyhole limpet hemocyanin vaccine.
 23. The methodof claims 1-17, wherein the vaccine is pneumovax-23 vaccine.
 24. Themethod of any of claims 1-23, wherein the second dose is 0 mg fumarateagent.
 25. A method of treating or preventing a neurological disease ordisorder in a subject in need thereof, comprising (a) administering tothe subject a first dose of a pharmaceutical composition for a firstdosing period, wherein the pharmaceutical composition comprises afumarate agent selected from the group consisting of monomethylfumarate, a compound that metabolizes into monomethyl fumarate in vivo,a deuterated analog thereof, a pharmaceutically acceptable salt thereof,and a combination thereof, wherein the subject receives a vaccine; (b)determining an immune response of the subject to the vaccine before theend of the first dosing period; and (c) administering to the subject asecond dose of the pharmaceutical composition for a second dosingperiod, wherein the second dose is equal to or less than the first dose.26. The method of claim 25, wherein the neurological disease or disorderis multiple sclerosis.
 27. The method of claim 25 or 26, wherein thefumarate agent is monomethyl fumarate, dimethyl fumarate, or acombination thereof.
 28. The method of any of claims 25-27, wherein thefumarate agent is dimethyl fumarate.
 29. The method of claim 28, whereinthe first dose is a daily amount of about 480 mg dimethyl fumarate. 30.The method of any of claims 25-29, wherein the second dose is 0 mgfumarate agent.
 31. The method of any of claims 25-30, furthercomprising administering a titration dose of the pharmaceuticalcomposition prior to the first dosing period.
 32. The method of claim31, wherein the fumarate agent is dimethyl fumarate and the titrationdose is a daily amount of about 240 mg dimethyl fumarate.
 33. The methodof any of claims 25-32, wherein the first and second doses of thefumarate agent are in a form of microtablets, micropellets, granules,capsules, or tablets.
 34. The method of any of claims 25-33, wherein thedimethyl fumarate is in a form of microtablets, and wherein themicrotablets are enterically coated.
 35. The method of any of claims25-34, wherein the subject receives the vaccine about 2 to 4 weeksbefore the start of the first dosing period, or during the first dosingperiod.
 36. The method of any of claims 25-35, wherein the subjectreceives the second dose of the fumarate agent following the end of thefirst dosing period.
 37. The method of any of claims 25-36, wherein thevaccine induces a T-cell dependent immune response.
 38. The method ofany of claims 25-37, wherein the vaccine induces a T-cell independentimmune response.
 39. The method of any of claims 25-38, wherein theimmune response of the subject to the vaccine is characterized in thatthe serum antibody level induced by the vaccine in the subject increasesless than 4-fold from pre-vaccination to 4 weeks after vaccination, andthe second dose is less than the first dose.
 40. The method of any ofclaims 25-39, wherein the immune response of the subject to the vaccineis characterized in that the serum antibody level induced by the vaccinein the subject increases at least 2-fold from pre-vaccination to 4 weeksafter vaccination, wherein the second dose is the same as the firstdose.
 41. The method of any of claims 25-40, wherein the immune responseof the subject to the vaccine is characterized in that the scrumantibody level induced by the vaccine in the subject is lower comparedto average serum antibody level induced by the vaccine in subjectsadministered with the vaccine but no fumarate agent, and the second doseis less than the first dose.
 42. The method of any of claims 25-41,wherein the vaccine is a live or inactive vaccine.
 43. The method ofclaim 42, wherein the vaccine is an inactive vaccine.
 44. The method ofany of claims 25-41, wherein the vaccine is a vaccine selected from thegroup consisting of tetanus diphtheria toxoids vaccine, keyhole limpethemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof.45. The method of any of claims 25-41, wherein the vaccine is tetanusdiphtheria toxoids vaccine.
 46. The method of any of claims 25-41,wherein the vaccine is keyhole limpet hemocyanin vaccine.
 47. The methodof claims 25-41, wherein the vaccine is pneumovax-23 vaccine.
 48. Amethod of treating or preventing a neurological disease or disorder in asubject who receives a vaccine, comprising: (a) screening a plurality ofdoses of a pharmaceutical composition comprising a fumarate agentselected from the group consisting of monomethyl fumarate, a compoundthat metabolizes into monomethyl fumarate in vivo, a deuterated analogthereof, a pharmaceutically acceptable salt thereof, and a combinationthereof, by (1) identifying a first group of subjects and at least asecond group of subjects, wherein both the first and second groups ofsubjects receive the vaccine while treated with the fumarate agent,wherein the first group of subjects is treated with a first dose of thefumarate agent, and the second group of subjects is treated with asecond dose of the fumarate agent; (2) determining a lower risk dose;and (b) administering the lower risk dose of the pharmaceuticalcomposition to the subject.
 49. The method of claim 48, wherein theneurological disease or disorder is multiple sclerosis.
 50. The methodof claim 48 or 49, wherein the fumarate agent is dimethyl fumarate. 51.The method of claim 50, wherein the first dose is a daily amount ofabout 480 mg dimethyl fumarate.
 52. The method of any of claims 48-51,wherein the second dose is 0 mg fumarate agent.
 53. The method of any ofclaims 48-52, further comprising administering a titration dose of thepharmaceutical composition to the subject.
 54. The method of any ofclaims 48-53, wherein the fumarate agent is dimethyl fumarate and thetitration dose is a daily amount of about 240 mg dimethyl fumarate. 55.The method of claims 48-54, wherein the group of subjects treated withthe lower risk dose have higher proportion of subjects with at least2-fold increase in serum antibody levels induced by the vaccine frompre-vaccination to 4 weeks after vaccination.
 56. The method of claims48-54, wherein the group of subjects treated with the lower risk dosehave higher proportion of subjects having serum antibody levels inducedby the vaccine not less than average scrum antibody level observed insubjects administered with the vaccine but no fumarate agent at 4 weeksafter vaccination.
 57. The method of any of claims 48-56, wherein thevaccine is a live or inactive vaccine.
 58. The method of claim 57,wherein the vaccine is an inactive vaccine.
 59. The method of any ofclaims 48-56, wherein the vaccine is a vaccine selected from the groupconsisting of tetanus diphtheria toxoids vaccine, keyhole limpethemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof.60. The method of any of claims 48-56, wherein the vaccine is tetanusdiphtheria toxoids vaccine.
 61. The method of any of claims 48-56,wherein the vaccine is keyhole limpet hemocyanin vaccine.
 62. The methodof claims 48-56, wherein the vaccine is pneumovax-23 vaccine.
 63. Themethod of any of claims 48-62, wherein the lower risk dose is the seconddose, wherein the second dose is less than the first dose.
 64. A methodof treating or preventing multiple sclerosis in a subject in needthereof, comprising (a) determining a subject's baseline lymphocytecount prior to treatment; (b) administering to the subject a first doseof a pharmaceutical composition for a first dosing period, wherein thepharmaceutical composition comprises a fumarate agent selected from thegroup consisting of monomethyl fumarate, a compound that metabolizesinto monomethyl fumarate in vivo, a deuterated analog thereof, apharmaceutically acceptable salt thereof, and a combination thereof; (c)determining a subject's total lymphocyte count after the first dosingperiod; and (d) if the lymphocyte count after the first dosing period isabout 90% of the baseline lymphocyte count or lower, do not administertetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine,pneumovax-23 vaccine, or any combinations thereof.
 65. The method ofclaim 64, wherein the subject's lymphocyte count is 70% of the baselinelymphocyte count or lower.
 66. The method of claim 64, wherein thesubject's lymphocyte count is 50% of the baseline lymphocyte count orlower.
 67. The method of any of claims 64-66, wherein the fumarate agentis monomethyl fumarate, dimethyl fumarate, or a combination thereof. 68.The method of claims 64-66, wherein the fumarate agent is dimethylfumarate.
 69. The method of claim 67, wherein the first dose is a dailyamount of about 480 mg dimethyl fumarate.
 70. The method of any ofclaims 64-69, further comprising administering to the subject a seconddose for a second dosing period.
 71. The method of claim 70, wherein thesecond dose is lower than the first dose.
 72. The method of claim 71,wherein the second dose is 0 mg fumarate agent.
 73. The method of any ofclaims 64-72, further comprising administering a titration dose of thepharmaceutical composition prior to the first dosing period.
 74. Themethod of claim 73, wherein the fumarate agent is dimethyl fumarate andthe titration dose is a daily amount of about 240 mg dimethyl fumarate.75. The method of any of claims 70-74, wherein the first and seconddoses of the fumarate agent are in a form of microtablets, micropellets,granules, capsules, or tablets.
 76. The method of any of claims 64-75,wherein the dimethyl fumarate is in a form of microtablets, and whereinthe microtablets are enterically coated.
 77. The method of any of claims64-76, further comprising administering a vaccine, wherein the step ofadministering the vaccine occurs before or during the first dosingperiod.
 78. The method of claim 77, wherein the vaccine induces a Tcell-dependent immune response.
 79. The method of claim 77, wherein thevaccine induces a T cell-dependent anamnestic humoral immune response.80. The method of claim 77, wherein the vaccine induces a Tcell-dependent neoantigen immune response.
 81. The method of claim 77,wherein the vaccine induces a T cell-independent immune response. 82.The method of any of claims 77-81, wherein serum antibody level inducedby the vaccine in the subject is lower compared to average serumantibody level observed in subjects administered with the vaccine butnot the fumarate agent, and the second dose is less than the first dose.83. The method of any of claims 77-81, wherein scrum antibody levelinduced by the vaccine in the subject increases less than 4-fold frompre-vaccination to 4 weeks after vaccination, and the second dose isless than the first dose.
 84. The method of any of claims 77-81, whereinthe vaccine is a live or inactive vaccine.
 85. The method of claim 84,wherein the vaccine is an inactive vaccine.
 86. The method of any ofclaims 77-85, wherein the vaccine is a vaccine selected from the groupconsisting of tetanus diphtheria toxoids vaccine, keyhole limpethemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof.87. The method of claim 86, wherein the vaccine is tetanus diphtheriatoxoids vaccine.
 88. The method of claim 86, wherein the vaccine iskeyhole limpet hemocyanin vaccine.
 89. The method of claim 86, whereinthe vaccine is pneumovax-23 vaccine.
 90. The method of any of claims70-89, wherein the second dose is 0 mg fumarate agent.
 91. A method oftreating multiple sclerosis in a human subject in need thereofcomprising (a) administering a therapeutically effective amount ofdimethyl fumarate to the subject; and (b) administering a vaccine to thesubject.
 92. The method of claim 91, wherein the therapeuticallyeffective amount of dimethyl fumarate is a maintenance dose that isrepeatedly administered over at least a period of time, and said step(b) of administering said vaccine is during said period of time.
 93. Themethod of claim 91 or 92, wherein the maintenance dose is orallyadministered 240 mg dimethyl fumarate twice daily.
 94. The method of anyof claims 91-93, wherein the period of time is 1 week.
 95. The method ofany of claims 91-93, wherein the period of time is 6 months.
 96. Themethod of any of claims 91-95, wherein the immune response to saidvaccine is decreased in said subject relative to the immune response inthe absence of said step (a) of administering a therapeuticallyeffective amount of dimethyl fumarate.
 97. The method of any of claims91-96, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 98. The method of claim 97, wherein the multiple sclerosis isrelapsing-remitting multiple sclerosis.